Compensatory responses to glaucoma pathology in the dorsolateral geniculate nucleus

Shaylah McCool; Arnav Jain; Jennie C Smith; Victoria Schaal; Gurudutt Pendyala; Sowmya Yelamanchili; Matthew J Van Hook

doi:10.1016/j.isci.2026.115176

. 2026 Feb 28;29(4):115176. doi: 10.1016/j.isci.2026.115176

Compensatory responses to glaucoma pathology in the dorsolateral geniculate nucleus

Shaylah McCool ^1,², Arnav Jain ¹, Jennie C Smith ¹, Victoria Schaal ³, Gurudutt Pendyala ^3,^4,^5,⁶, Sowmya Yelamanchili ^3,^4,⁵, Matthew J Van Hook ^1,^7,^8,^∗

PMCID: PMC12995702 PMID: 41858631

Summary

Glaucoma disrupts the conveyance of retinal signals to visual regions of the brain such as the dorsolateral geniculate nucleus (dLGN) due to degeneration of retinal ganglion cells (RGCs) and their axons. Although plasticity during development allows altered visual experience to modulate dLGN synapses and excitability, evidence for experience-dependent dLGN plasticity in adults is limited. However, glaucoma might trigger compensatory plasticity in adult dLGN, thereby compensating for diminished RGC synaptic drive. Here, we tested this theory using aged DBA/2J mice, which develop high intraocular pressure and glaucoma. In brain slice recordings, we found that diminished RGC inputs could drive robust action potential firing in dLGN relay neurons that was comparable to controls. This was accompanied by increased intrinsic excitability and decreased magnitude of sustained inhibitory currents from delta subunit-containing GABA receptors. These results implicate multiple cellular and synaptic mechanisms that support signaling despite the diminished RGC inputs in glaucoma.

Subject areas: pathology, molecular neuroscience, sensory neuroscience

Graphical abstract

Highlights

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Retinogeniculate synapse strength is diminished in DBA/2J mice with glaucoma
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Diminished retinogeniculate synapses drive robust firing in dLGN relay neurons
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Increased relay neuron intrinsic excitability supports action potential generation
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Reduced sustained inhibition also supports action potential firing

Pathology; Molecular neuroscience; Sensory neuroscience

Introduction

The dorsolateral geniculate nucleus (dLGN) of the thalamus is a critical waypoint for information traveling from the retina to the primary visual cortex (V1) for conscious vision.¹^,²^,³ In the dLGN, retinal ganglion cells make strong, high release probability excitatory synapses onto thalamocortical (TC) relay neurons. TC neurons integrate those inputs along with feedforward inhibition from local interneurons, feedback inhibition from thalamic reticular nucleus, and excitation from layer 6 of V1 to drive action potential output. Synaptic and neuronal function in the developing dLGN is subject to experience-dependent plasticity during a critical period occurring around postnatal days 20–35 in mice.⁴^,⁵ During this time frame, altered visual experience—such as dark rearing or monocular deprivation—can modulate the developmental refinement of retinogeniculate synapses,⁶^,⁷^,⁸^,⁹ corticothalamic feedback,¹⁰ and intrinsic excitability.¹¹ The adult dLGN appears to be considerably less plastic, which is likely important for stable visual encoding.⁹^,¹² However, several examples indicate that dramatic disruptions to visual experience might trigger plasticity of dLGN and TC circuits,¹³^,¹⁴ potentially similar to ways that injury or stroke in cortex opens a developmental-like period of plasticity.¹⁵ Such re-awakening of adult plasticity potentially permits intrinsic repair mechanisms and pharmacological approaches to activate development-like critical periods might be a viable therapeutic approach under various disease or injury conditions.¹⁵^,¹⁶

Glaucoma is an ocular disease commonly associated with elevated intraocular pressure (IOP) due to reduced aqueous humor outflow from the anterior chamber.¹⁷ The increase in IOP damages retinal ganglion cell (RGC) axons, ultimately leading to RGC degeneration and cutting off the route for retinal signals to reach visual centers of the brain, including the RGC-dLGN-V1 pathway.¹⁸^,¹⁹^,²⁰ We have recently mapped the time course of this process in DBA/2J (D2) mice,¹⁹ a commonly used rodent model of glaucoma with age-dependent IOP elevation and RGC loss.²¹^,²²^,²³ These mice have a progressive IOP-associated loss of RGC axon terminals in the dLGN accompanied by functional declines in RGC-to-TC neuron synaptic transmission.¹⁹^,²⁴

Blindness and visual impairment arising from age-associated progressive disorders such as glaucoma might re-awaken dLGN plasticity and serve to re-shape dLGN function. Indeed, evidence from human glaucoma patients supports the possibility that the brain adapts to glaucomatous vision loss to preserve binocular visual fields.²⁵ Our prior work has pointed to several potentially adaptive responses in the dLGN accompanying IOP elevation and optic nerve injury. For instance, we have found enhanced action potential firing in TC neurons following experimental IOP elevation using anterior chamber microbead injections and in TC neurons from 9-month-old D2 mice.²⁴ In both, measures of TC neuron excitability correlated with eye pressure, suggesting a functional link. Bilateral enucleation of adult mice likewise led to loss of RGC-TC neuron synapses accompanied by increased TC neuron intrinsic excitability.²⁶ These and other unexplored effects of high IOP and optic nerve injury on TC neurons are potentially homeostatic adaptations to glaucoma in that they might allow TC neurons to convey visual signals to V1 despite the diminished input from RGCs, but this possibility has not been tested.

The goal of the current study was to test whether and how glaucoma impacts TC neuron transformation of RGC synaptic inputs into action potential output. Specifically, we sought to determine whether effects on TC neurons are consistent with homeostatic compensation in response to the decline in retinogeniculate synaptic drive in aged D2 mice. We found that TC neurons from aged D2 mice generate robust synaptically driven action potential output despite diminished retinogeniculate synaptic strength, consistent with compensatory upregulation of intrinsic excitability. This appears to be linked to augmented action potential generation mechanisms as well as diminished levels of sustained inhibition at delta (δ) subunit-containing GABA_A receptors. These results suggest that dLGN circuits and TC neuron intrinsic function might support sustained dLGN-to-V1 transmission despite the IOP-dependent diminishment of RGC inputs to the dLGN.

Results

Intraocular pressure and glaucoma pathology in DBA/2J mice

Intraocular pressure (IOP) is a key risk factor in glaucoma,¹⁷ which leads to decreased RGC signaling to the dLGN,¹⁹ a major thalamic relay for conscious vision. Monthly IOP measurements from DBA2J (D2) mice and their age-matched controls (D2-control) showed higher peak IOP in D2 mice indicating increased pressure on D2 retinal ganglion cells (RGCs) and their axons which make up the optic nerve (Figure 1A). Female D2 eyes had higher peak IOP values than in males (p = 0.00004, t test), which is consistent with prior work.¹⁹^,²¹ To examine the optic nerve more closely, glial scarring was analyzed in cross sections of optic nerve tissue (Figures 1B and 1C). Percentage of optic nerve that was glial scar was significantly higher in D2 mice indicating damage to the optic nerve and matching previous findings.²⁷^,²⁸^,²⁹ Within the D2 population, there was more glial scarring apparent in nerves from female D2 mice compared to males, consistent with the higher IOP (p = 0.018, t test). Since there was significant glial scarring of the optic nerve in the D2 model, we tested whether RGC function was altered using pattern electroretinogram (pERG) recordings (Figures 1D and 1E), finding that D2 mice showed reduced pERG P1 and N2 amplitudes compared to controls, consistent with prior findings.³⁰ We did not detect an effect of sex on pERG amplitudes among D2 mice. Log-transformed P1 pERG amplitudes correlated significantly with IOP, and P1 pERG amplitudes weakly but significantly correlated with the extent of optic nerve glial scar (Figures 1F and 1G). Likewise, there was a significant correlation of glial scar with IOP (R² = 0.34, p = 0.0051; Figure S1).

Diminished retinogeniculate synapses drive robust action potential output in DBA/2J TC neurons

We have shown previously that D2 mice have reduced strength of RGC synaptic output to post-synaptic dLGN TC neurons.¹⁹^,²⁴ We therefore sought to relate how this reduction in RGC synaptic strength impacts synaptically driven TC neuron action potential firing (Figure 2). To accomplish this, we used a potassium-based pipette solution to switch between voltage clamp and current clamp while recording from individual dLGN TC neurons. Retinogeniculate synaptic inputs and action potential output were measured in this way in response to optic tract stimulation using a stimulus sequence derived from RGC spiking activity (Figure 2A). Although this was derived from a specific ganglion cell, the sequence was merely intended to represent a somewhat closer to “physiological” stimulus pattern than single or paired pulses or fixed frequency pulse trains, and not to perfectly capture the in vivo pattern of RGC spiking, similar to what has been used in other work.³¹^,³² Integrated charge of the excitatory postsynaptic currents (EPSCs) was reduced in D2 mice and matched the extent of reduction of EPSC amplitude (∼65%) from our prior findings.¹⁹ Also like our prior findings, EPSC charge had a weak negative correlation with IOP, with higher maximum IOP being associated with weaker retinogeniculate synaptic strength (p = 0.020, R² = 0.14). This is consistent with the declines in single-vesicle EPSC frequency we found previously¹⁹^,²⁴ supporting a reduction in retinogeniculate drive at this time point. We did not detect effects of sex on EPSC amplitude within the D2 population (p = 0.65, t test). Despite the dramatic diminishment of retinogeniculate synaptic drive, the overall number of action potentials fired during the stimulus sequence was nearly identical between D2 and D2-controls across the population of recorded TC neurons (Figure 2B). We also did not detect any significant difference between D2-control and D2 recordings in the decay kinetics of the excitatory postsynaptic potentials (p = 0.82, nested t test) and there was no significant difference between D2-control and D2 recordings for either first spike latency or first spike jitter, although both measures trended higher in D2 recordings and the variance for both measures was higher in D2 recordings (Figure S2). This might arise from differential effects of glaucoma on the different RGC subtypes providing input to TC neurons. There was considerable cell-to-cell variability in the total number of fired action potentials, as is apparent in Figures 2B and S2 and is consistent with prior work from our group and others.³¹^,³² We related the TC neuron action potential output to the strength of the retinogeniculate synaptic input by quantifying the total number of action potentials fired per pC of EPSC charge integrated over the stimulus sequence, finding that this ratio was higher in D2 mice compared to D2-controls (Figure 2C). Thus, although D2 mice with increased IOP have optic nerve damage and diminished RGC drive to post-synaptic TC neurons, those TC neurons appear to more efficiently transform that decreased synaptic input into robust action potential output.

Diminished retinogeniculate synapses continue to drive robust action potential output in TC neurons from D2 mice

(A) Example traces of current- and voltage-clamp recordings from TC neurons with a “physiological” optic tract stimulus.

(B) Scatterplot of EPSC charge (integrated over the stimulus train) and number of action potentials for individual cells. EPSC charge was approximately 65% lower in D2 mice compared to controls [∗∗∗∗p < 0.0001 (EPSC) via nested t test of log transformed data] while the total number of action potentials fired over the stimulus train was similar (n.s., p = 0.92 [# of spikes] via nested t test; n = 16 cells, five mice [D2-control] and n = 23 cells, six mice [D2]). Group data (dark data points and error bars) are shown as mean ± SEM.

(C) Quantification of synaptically driven spikes per pC of EPSC charge input shows increased efficiency of synaptically driven action potential firing in D2 mice compared to controls (∗p = 0.021 via nested t test of log-transformed data). Dark lines and error bars show median ± IQR. n = 16 cells, five mice (D2-control) and n = 23 cells, six mice (D2).

Plasticity of intrinsic excitability in D2 mice

One possible mechanism by which TC neurons in D2 mice might accomplish this is via enhanced intrinsic excitability. Step depolarizations and hyperpolarizations in whole cell current-clamp recordings were used to measure action potential firing and passive membrane properties of the TC neurons (Figures 3A and 3B). These experiments revealed that D2 TC neurons were more intrinsically excitable than those from D2-controls, as evidenced by a left-shift of the frequency-current (F-I) curves in the D2 TC neurons as well as increased incidences of depolarization block at stronger current injections (Figures 3A–3C). These results in older D2 mice are consistent with what we have found at a younger time point.²⁴ There was also a significant relationship with retinogeniculate synaptic integrity and intrinsic excitability, with the TC neurons that showed weaker retinogeniculate synaptic strength tending to fire a greater number of action potentials in response to a step current injection (+80 pA; R² = 0.30, p = 0.0007; Figure 3D). This supports a relationship between the loss of presynaptic inputs and a homeostatic enhancement of intrinsic excitability of the post-synaptic TC neurons. Passive membrane properties were measured including resting membrane potential (V_rest), input resistance (R_in), and membrane capacitance (C_m; Figures 3E–3H). The mean resting membrane potential was not significantly different between D2-control and D2 mice, although there was significantly higher variability across the population of recorded D2 TC neurons (F test, p = 0.0015). Within the D2 population, TC neurons from female D2 mice had a more depolarized V_rest than those from males (p = 0.0047, t test). Excitability appeared at least partially related to resting membrane potential, as the number of evoked action potentials at the +80 pA step significantly correlated with V_rest (R² = 0.48, p < 0.0001; Figure 3F). Hyperpolarizing steps were used to measure R_in, and there was no significant difference between D2-control and D2 mice, although variance was significantly higher in the D2 group (F test, p = 0.0021). R_in was higher in TC neurons from D2 females compared to those from D2 males (p = 0.012, t test). C_m was measured in voltage-clamp recordings by integrating the membrane capacitance transient in response to a −10 mV step. C_m was significantly lower in D2 TC neurons, likely indicative of decreased TC neuron membrane surface area. This finding is consistent with our measurements of lower Cm and somatic atrophy in 9-month-old D2 experiments and with the reduction in TC neuron dendritic complexity we have found in 12-month-old D2 TC neurons.¹⁹^,²⁴ There was a difference in C_m between TC neurons from male vs. female D2 mice, with those from females having a lower C_m (p = 0.015, t test), likely indicating more dramatic somatic atrophy and/or dendritic loss in TC neurons from female mice. This difference might arise from slight differences in the severity of glaucoma in female mice, as Cm very weakly but significantly correlated with IOP (R² = 0.053, p = 0.024). We next studied action potential properties while maintaining resting potential at approximately −60 mV to inactivate low voltage-activated Ca²⁺ currents,³² which contribute to TC neuron rebound spiking.³³^,³⁴^,³⁵ Using a 500 pA ramp current injection (Figures 3I–3K), we measured TC neuron action potential threshold and rheobase, finding that TC neurons from D2 mice had a lower action potential threshold and lower rheobase. Threshold was slightly lower in TC neurons from D2 females compared to D2 males (p = 0.029, t test), although we did not detect a sex difference in rheobase (p = 0.31).

Overall, these data indicate that TC neurons from D2 mice are more excitable, as indicated by (1) an increased readiness to fire action potentials in response to stimulation, (2) the increased incidence of depolarization block, (3) the shift in action potential threshold, and (4) a reduction in rheobase. While the correlation of excitability with V_rest points to a functional link, using current clamp to maintain resting potential indicates that the increased excitability is partially independent of effects on V_rest.

Altered action potential generation mechanisms in D2 mice

The axon initial segment (AIS) is the structure responsible for initiating action potentials due to its high density of voltage-gated sodium channels.³⁶^,³⁷ AIS length can be modulated in some neuron populations as an apparent mechanism to homeostatically regulate intrinsic excitability.³⁸^,³⁹ IOP-induced alterations in AIS length in mice with glaucoma might underlie changes in TC neuron excitability in D2 mice. To test this, we performed immunostaining for Ankyrin-G, a scaffolding protein found in the AIS, to determine the size of the AIS in TC neurons (Figures 4A and 4B). We manually measured the AIS length in images obtained from Ankyrin-G-stained dLGN slices. Overall, AIS length was similar and not significantly different when comparing between measurements from D2 and D2 control dLGN sections. Thus, modulation of AIS length in dLGN TC neurons is unlikely to underlie their altered excitability in D2 mice.

To further examine the relationship between the TC neurons and action potential generation, we analyzed action potential waveforms via phase plots.⁴⁰ Taking the first derivative of the action potential waveform and plotting it against voltage allows us to examine different features of the action potential (Figures 4C–4F). We found a hyperpolarized shift in action potential threshold in TC neurons from D2 mice, consistent with experiments using the ramp stimulus, above. In this analysis, we detected a slightly more hyperpolarized action potential threshold (−57.8 ± 1.8 mV) in a set of recordings (five cells from two mice, p = 0.042, nested t test, 14.5 months of age) compared to the rest of the cells, which were from approx. 12 month-old mice (30 cells from eight mice, −52.2 ± 0.8 mV). There was a significant increase in peak slope of the rising phase of action potentials in D2 TC neurons (max dv/dt) with a trending but not statistically significant effect (p = 0.051) on the peak slope of the falling phase (min dv/dt). There was a weak but significant correlation of both max dv/dt and min dv/dt with the peak IOP (max dv/dt, R² = 0.19, p = 0.001; min dv/dt, R² = 0.14, p = 0.004; Figure S3). Next, we looked at current flow responsible for charging the membrane (-C_m∗dv/dt) during TC neuron action potentials (Figures 4G and 4H).⁴¹^,⁴² Both the inward and outward current amplitudes were comparable between D2-control and D2 mice, with no significant difference between groups. We did not detect a significant difference by sex for any of these parameters within the D2 population. These data suggest that voltage-gated Na⁺ or K⁺ channel expression in dLGN TC neurons is not altered in D2 mice. This is supported by examination of a prior RNA-sequencing dataset⁴³ from bulk dLGN tissue samples from 9-month-old D2 and D2-control mice where there was no significant change in expression of key Na_V or K_V genes (Figure S3). Together, these results indicate that although the total membrane current is the same, the lower C_m (Figure 3F) of D2 TC neurons leads to an increased current density of Na⁺ and K⁺ currents, likely contributing to enhanced action potential generation.

Feedforward inhibition is more transient in the DBA/2J dLGN

In addition to effects on intrinsic excitability, altered synaptic properties such as reduced synaptic inhibition might support TC neuron action potential firing driven by excitatory synaptic input. To test this possibility, TC neuron excitatory and inhibitory post-synaptic currents (EPSCs and IPSCs) were measured in response to a physiological train of optic tract stimulation like that used in Figure 2, except using a Cs-based pipette solution (Figure 5A). In this approach, EPSCs represent monosynaptic excitatory drive from RGC axons while the IPSCs are the result of disynaptic feedforward inhibition arising from local interneurons.¹^,⁴⁴ We found that EPSCs in brain slices from D2 mice were reduced in amplitude compared to D2-controls, as above (Figure 2) and in keeping with our prior findings.¹⁹ IPSCs from D2-controls were relatively sustained but showed a faster decay back to baseline in slices from D2 mice. To quantify this, we used a single stimulation of the optic tract while recording IPSCs (Figure 5B). These IPSCs were entirely blocked by the GABA_A receptor blocker 25 μM SR95531 (n = 6 cells, 100 ± 2% reduction in amplitude, Figure S4) indicating appropriate voltage clamp isolation of inhibitory currents. The decay of the IPSCs could be fit with a sum of two exponential functions, and while the time constants themselves were not significantly different between D2 and D2-control TC neurons, there was a relative decrease in the percentage of the decay mediated by the slow time constant (Figures 5C and 5D), and this did not differ by sex within the D2 population (p = 0.6, t test).

Feedforward inhibition is more transient in the D2 mouse

(A) Mean ± SEM traces of monosynaptic retinogeniculate excitatory postsynaptic currents (EPSCs, “excitation”) and feedforward disynaptic inhibitory post-synaptic currents (IPSCs, “inhibition”) driven by optic tract stimulation and recorded from TC neurons in D2 (red) and D2-control (gray) dLGN slices (n = 9 cells from three mice [D2-control] and n = 23 cells from seven mice [D2]).

(B) Example feedforward IPSC traces following single optic tract stimulation illustrating faster decay kinetics in the D2 recording.

(C) Decay time constants show no difference between D2 (red) and D2-control (gray) mice following single optic tract stimulation (n.s., p = 0.063 [fast time constant] and n.s., p = 0.65 [slow time constant] via nested t test of log transformed values; n = 31 cells, nine mice [D2] and n = 23 cells, nine mice [D2-control]). Bar graphs and error bars show mean ± SEM.

(D) Percentage of decay made up of slow time constant is lower in D2 mice (red) compared to controls (gray) following optic tract stimulation. (∗∗∗p = 0.0020 via nested t test; n = 31 cells, nine mice [D2] and n = 23 cells, nine mice [D2-control]). Bar graphs and error bars show mean ± SEM.

(E) Example IPSC traces in response to stimulation delivered by an aCSF-filled pipette located approximately 25 microns from the recorded TC neuron in the presence of CNQX and D-AP5.

(F) Decay time constants show no difference between D2 (red) and D2-control (gray) mice following local stimulation. (n.s., p = 0.41 [fast time constant] and n.s., p = 0.62 [slow time constant] via nested t test; n = 11 cells, seven mice [D2] and n = 13 cells, eight mice [D2-control]). Bar graphs and error bars show mean ± SEM.

(G) Percentage of decay made up of the slow time constant is lower in D2 mice (red) compared to controls (gray) following local stimulation (∗p = 0.029 via paired t test; n = 11 cells, seven mice [D2] and n = 13 cells, eight mice [D2-control]). Bar graphs and error bars show mean ± SEM.

Although this stimulus approach allowed us to record inputs from local interneurons, it is potentially confounded by glaucomatous alterations of RGC-to-interneuron synaptic function. Therefore, we recorded monosynaptic IPSCs while bypassing the RGCs by directly stimulating interneurons with an extracellular electrode positioned in the dLGN approx. 25 microns from the recorded TC neurons (Figure 5E). The aCSF was supplemented with glutamatergic blockers (CNQX, D-AP5) to further isolate inhibitory inputs in the absence of RGC inputs. IPSCs were completely blocked by the GABA_A receptor blocker SR95531 (25 μM, n = 10 cells; 99 ± 1% reduction) and unaffected by application of the GABA_B receptor blocker CGP55845 (0.81 ± 5% reduction, n = 6 cells; Figure S5). Similar to above, the decay of IPSCs recorded in this way was well-fit with a sum of two exponential functions. Although fast and slow time constants were similar between D2 and D2-control recordings, the D2 recordings showed a reduction in the relative percentage of the decay mediated by the slow time constant (Figures 5F and 5G), and this was more pronounced in TC neurons from female D2 mice compared to male D2 mice (p = 0.032, t test). Overall, these results show that feedforward inhibition is more transient in TC neurons from D2 mice. This effect on sustained inhibition likely contributes, alongside the enhanced intrinsic excitability, to enhanced TC neuron action potential generation during optic tract stimulation.

Decreased activation of extrasynaptic GABA_A receptors in DBA/2J TC neurons

We next employed pharmacological manipulations to investigate GABAergic signaling in the dLGN. Within the thalamus, GABA acts extrasynaptically on δ subunit-containing GABA_A receptors.⁴⁵^,⁴⁶^,⁴⁷ The relative reduction in the slow component of the IPSC decay might be the result of diminished extrasynaptic GABA effects.⁴⁸^,⁴⁹ We therefore tested whether DS2, a positive allosteric modulator of δ subunit-containing GABA_A receptors,⁵⁰ had differential effects on TC neuron IPSCs from D2 vs. D2-control mice (Figure 6A). DS2 (10 μM) evoked an outward current of 171 ± 25 pA in D2-control TC neurons and 119 ± 7 pA in D2 TC neurons, but this difference was not statistically significant (p = 0.061, nested t test; Figure S6). We again recorded IPSCs from dLGN TC neurons in response to local extracellular stimulation in the presence of CNQX and D-AP5 and found that DS2 enhanced the slower components of the IPSC. This effect was more pronounced in recordings from D2-controls compared to those from D2 mice (Figure 6B), implying a reduced contribution δ subunit-containing GABA_A receptors in D2 TC neurons.

We next investigated whether this could be attributable to differential GABA reuptake by astrocytes in D2 vs. D2-control dLGN. To test this, we applied the GABA transporter inhibitor SNAP5114 (60 μM), which is fairly selective for the astrocytic GAT-3 transporter,⁵¹^,⁵²^,⁵³ while again measuring IPSCs evoked by local stimulation (Figure 6C). SNAP5114 had no effect on IPSC peak amplitude but led to an increase in IPSC area due to enhancement of later portions of the IPSC. However, the relative change in the sustained portion of the IPSC by SNAP5114 was similar in D2 and D2-control recordings (Figure 6D), implying that astrocytic GABA uptake is similar in control mice and mice with glaucoma. Together, these results suggest a decrease in δ subunit-mediated GABAergic inhibition in dLGN TC neurons of D2 mice, likely supporting enhanced action potential firing in response to diminished excitatory synaptic drive from RGCs.

Discussion

In healthy mouse dLGN, 1–3 RGC inputs provide the major excitatory input drive for TC neuron spike output, with a threshold of approximately 600 pA EPSC amplitude needed to trigger a TC neuron action potential.⁵⁴^,⁵⁵^,⁵⁶ A loss of retinogeniculate synaptic input in the glaucomatous dLGN¹⁹ would therefore be predicted to diminish the efficiency of TC neuron action potential output. However, the major finding of this study is that dLGN TC neurons in aged D2 mice can efficiently transform RGC excitatory synaptic inputs into action potential output despite the diminished strength of those inputs. This occurs at an age where these mice show clear signs of glaucoma including high IOP, optic nerve pathology, and declining pERG responses, among numerous other pathological signs documented in previous studies by our group and others.¹⁹^,²¹^,²⁴^,²⁷^,²⁸^,²⁹^,³⁰^,⁵⁷^,⁵⁸^,⁵⁹^,⁶⁰^,⁶¹^,⁶²^,⁶³^,⁶⁴ We attribute this to a combination of increased intrinsic excitability - likely the result of an interplay between both increased voltage-gated channel density due to smaller membrane surface area and effects on other passive membrane properties—and reduced sustained inhibition from δ subunit-containing GABA receptors. Notably, there was a clear relationship between the strength of retinogeniculate synaptic inputs and measures of intrinsic excitability, with TC neurons receiving weaker retinogeniculate input being more intrinsically excitable, as might be predicted if intrinsic excitability is an adaptive response to synapse loss. We have found changes in TC neuron intrinsic excitability in 9-month-old D2 mice previously²⁴ and the current study demonstrates a similar phenomenon in older mice and expands far beyond that study to examine the underlying mechanisms and test how those excitability changes combine with effects on synaptic inhibition to impact TC neuron transformation of diminished synaptic inputs¹⁹ to action potential output.

Although there are three morphological types of dLGN TC neurons with different spatial distributions in the dLGN, they are not readily distinguishable by intrinsic physiology,⁶⁵ and we did not employ dye fills during whole cell recording. For some recorded TC neurons, RGC inputs and TC neuron intrinsic excitability were similar to D2-control recordings. However, D2 recordings show considerably more variability than observed in D2-controls, similar to our prior findings.¹⁹ Some of this might result from different extents of disease progression from mouse-to-mouse—a possibility supported by correlation of synaptic or intrinsic excitability parameters with IOP, differential effects of glaucoma on different RGC populations,⁶⁶^,⁶⁷ differential effects of glaucoma on different retinal regions,⁶⁸ or perhaps a combination of factors. In several measured parameters, we detected differences between recordings from TC neurons from male vs. female D2 mice, which might result from the higher overall IOP in female D2 mice.¹⁹^,²¹ Future studies should be designed and powered to specifically examine sex differences within the D2 population.

The current study also sought to distinguish the features of enhanced TC neuron intrinsic excitability in D2 mice - whether it is simply the result of passive properties such as increased R_in and depolarized V_rest or could be attributed to active spike generation mechanisms. While we did not find a significant difference in V_rest or R_in between D2 and D2-controls, similar to what we showed previously in younger (9-month old) D2 mice,²⁴ both measures were significantly more variable in D2 recordings, suggesting considerable heterogeneity across the population of TC neurons, even within individual mice. Although action potential generation was related to V_rest, the effects on V_rest were clearly not the sole contributor, as experiments where we controlled V_rest using stable current injections revealed lower action potential threshold and rheobase in D2 mice. The lower threshold and rheobase might suggest plasticity of TC neuron axon initial segments, which are densely packed with Na⁺ channels and critical for action potential generation. AIS length can be a locus for plasticity of intrinsic excitability in neurons in other brain regions.³⁷^,³⁹^,⁶⁹^,⁷⁰ In dLGN TC neurons, the concentration of K⁺ channels in the AIS has been shown to be associated with developmental plasticity of TC neuron excitability.¹¹ Here, however, AIS length was similar between D2 and D2-control mice. In the current study, analysis of action potential waveforms and the membrane currents responsible for charging the TC neuron membrane during the action potential showed that while the absolute amplitudes of currents were the same when comparing D2 and D2-control recordings, the D2 TC neurons had a smaller Cm, consistent with our prior work showing TC neuron somatic atrophy and reduced Cm in 9-month-old mice and lost dendritic complexity in 12-month-old D2 mice, leading to a higher current density. A fresh examination of our previously published bulk RNA sequencing data⁴³ showed no significant change in gene expression for voltage-gated Na⁺ or K⁺ channels between D2 and D2-control dLGN samples. Although those data were obtained from younger mice (approx. 9 months old) than those in the current study, mice at that time point showed a similar enhancement of intrinsic excitability. The distance of the AIS from the soma can be homeostatically regulated⁷¹ and this raises the possibility for the AIS-to-soma distance being dynamically regulated in response to glaucoma in dLGN TC neurons. Future work in dLGN should use TC neuron patch clamp recording in combination with dye fills and Ankyrin-G immunofluorescence staining to examine whether AIS-to-soma distance is altered in D2 mice and whether this relates to measured electrophysiological properties.

Overall, the findings here for older D2 mice are consistent with the patterns we found in younger animals. In addition to exploring whether these effects persist in this older age group, the current study expands this question to study additional facets of TC neuron action potential generation and relates those to effects on synaptically driven action potential firing. Compensatory changes in neuronal excitability might be a common effect of glaucoma through the visual pathway, as other work has demonstrated enhanced RGC excitability and altered Na⁺ channel expression in mouse glaucoma models.⁷²^,⁷³

The contributions of intrinsic action potential generation mechanisms to support synaptically driven spiking by TC neurons were complemented by alterations in sustained inhibition. dLGN TC neurons show considerable tonic inhibition and apparent GABA spillover from local interneurons that is attributable to activation of high-affinity δ subunit-containing extrasynaptic GABA_A receptors.⁴⁵^,⁴⁶^,⁴⁷^,⁵⁰^,⁷⁴^,⁷⁵ While there is no spillover component of single-vesicle quantal IPSCs,⁴⁷ our results show that DS2 enhanced a slow component of the multiquantal IPSC, consistent with GABAergic spillover. During a train or single stimulation of RGC inputs, feedforward inhibition from local interneurons generates a sustained inhibitory response in recorded TC neurons that is notably diminished in TC neurons from D2 mice. Measurements of IPSC kinetics along with experiments with DS2 point to involvement of extrasynaptic GABA_A receptors in the response to glaucoma in the dLGN and could be the result of fewer extrasynaptic receptors rather than increased GABA uptake by astrocytes as SNAP5114,⁵¹ a GABA transporter inhibitor, had led to a similar extent of enhancement of the sustained component of IPSCs in D2 and D2-controls. Such an effect could also result from altered GABA_A receptor subunit composition⁷⁶^,⁷⁷ or, potentially, from changes in the localization of δ subunit-containing GABAa receptors, as it is unclear whether glaucoma alters their localization in the dLGN.

Enigmatically, we have found previously that D2 mice show opposite effects on fast synaptic inhibition⁷⁸ compared to the effects on sustained inhibition here. In ∼12 month-old D2 mice, TC neurons have an apparent increase in synaptic GABA receptors, which leads to overall larger quantal IPSC amplitudes and larger local interneuron-driven multiquantal IPSCs than would be expected based on the extent of RG synapse loss. This seems at odds with a traditional “homeostatic” response to diminished excitatory drive from RGCs whereas the reduction in sustained inhibition seems to more clearly align with a mechanism for boosting action potential firing. Some evidence in other systems indicates that synaptic and extrasynaptic GABA receptor populations exist in dynamic competition with one another.⁷⁹^,⁸⁰ Still, we do not know what effect the combined increase in synaptic inhibition and decrease in extrasynaptic inhibition ultimately has on TC neuron output or “why” a TC neuron might boost synaptic inhibition while simultaneously diminishing the sustained response to GABA spillover. One possibility is that changing the balance of both forms of inhibitory input could contribute to TC neuron input selectivity or spiking precision in the face of weakened retinogeniculate inputs.⁴⁴^,⁴⁶^,⁸¹^,⁸²^,⁸³ In the dLGN, feedforward inhibition that is “locked” to the excitatory input, meaning that it arises from local interneurons driven by the same RGC axons driving the recorded TC neuron at the retinogeniculate glomerulus, increases spike precision and restricts the TC neuron to fire a single post-synaptic spike per presynaptic spike.⁴⁴ This is especially the case in TC neurons operating in a tonic firing mode (rather than burst mode, at more negative V_rest). In our recordings of synaptically driven spiking, first spike latency and first spike jitter were slightly higher in TC neurons from D2 mice although the difference compared to D2-controls was not significant. This might be indicative of intrinsic and/or synaptic mechanisms preserving spike precision, but whether this is actually the case will need further study - possibly with pharmacological or modeling approaches. In contrast, inhibition arising from RGC activation by RGCs not inputting onto a recorded TC neuron has been suggested to play a role in shaping TC neuron receptive field properties.⁸⁴^,⁸⁵^,⁸⁶ This also could be modulated by the shifted balance of phasic/sustained inhibition and merits future study.

Our results have implications for the broader understanding of plasticity in adult dLGN. Overall, the picture that emerges is one of homeostasis, with multiple cell-intrinsic and synaptic properties in dLGN TC neurons adapting to support synaptically driven action potential generation even as those synaptic inputs from RGCs decline due to RGC degeneration. Notably, we have not found evidence for homeostatic synaptic scaling on excitatory synapses with declining retinogeniculate synaptic strength in our prior studies.¹⁹^,²⁴ This is in contrast to developmental plasticity, which involves AMPA trafficking at retinogeniculate synapses.⁵⁵^,⁸⁷ Additionally, early monocular deprivation can impact corticothalamic feedback synapses, apparently via both pre- and post-synaptic mechanisms.¹⁰ Instead, glaucoma pathology appears to trigger effects on both inhibitory synapses and extrasynaptic sites, although changes in δ subunit-containing GABA_A receptor localization in the diseased dLGN might contribute to the altered sustained inhibitory response. Changes in TC neuron intrinsic excitability also contribute. There are relatively few examples of plasticity in adult dLGN, with most research being focused on experience-dependent plasticity during development. One study using longitudinal in vivo imaging of TC neuron axon terminals in binocular V1 following a brief monocular deprivation in adult mice showed an increase in response strength to stimulation of the non-deprived eye,⁸⁸ identifying a thalamic locus for some adult ocular dominance plasticity. Our findings of apparently homeostatic compensation in the adult glaucomatous dLGN add support to the notion of adaptive plasticity in the adult dLGN, although the effects clearly differ from those seen during dLGN maturation over the first few postnatal weeks in mice.

Prior work in D2 mice, including at ages comparable to those in the current study, points to glaucoma-associated declines in visual acuity,⁸⁹^,⁹⁰^,⁹¹ raising the question of what is accomplished by the compensation in the dLGN. It is possible that RGC pathology is too extensive at this time point such that its effects overwhelm any apparent circuit-level compensation in the dLGN. Alternatively, dLGN compensation might serve to lessen vision loss such that D2 mice would have even more pronounced visual performance deficits in the absence of dLGN compensation. Future studies that attempt to prevent dLGN compensation in D2 mice might, when combined with in vivo measures of visual behavior, be able to resolve these questions. Likewise, future measurements of thalamo-cortical synaptic function will be informative. Still, the question of visual system compensation in human glaucoma patients remains relevant. For instance, analyses of visual field data have shown that visual brain regions adapt in response to vision loss, with unilateral visual fields displaying complementary regions of loss such that binocular visual fields were preserved.²⁵ Compensatory responses to glaucoma occurring in retinal projection targets, such as the ones we have documented in the current study, might underlie or contribute to these vision-preserving adaptations seen in human patients, and this possibility merits further study.

While it is likely that high IOP and loss of RGC synapses are the ultimate triggers for the effects on dLGN inhibition and TC neuron excitability, we do not know what transduces these effects. Classically, Ca²⁺-dependent transduction pathways can detect altered activity levels and trigger intrinsic excitability changes and/or synaptic scaling—either throughout a neuron or at specific synapses.⁹² Glial cells, which are constantly surveilling the brain environment, might also contribute by detecting altered activity levels and releasing diffusible signals such as neurotrophins (i.e., BDNF) or cytokines (i.e., TNFα) that can trigger synaptic or intrinsic plasticity via transduction pathways.⁹³^,⁹⁴^,⁹⁵^,⁹⁶^,⁹⁷^,⁹⁸^,⁹⁹^,¹⁰⁰^,¹⁰¹^,¹⁰² Indeed, RGCs show increased intrinsic excitability in mouse glaucoma models and evidence points to TNFα as a regulator of RGC Na⁺ channel expression and excitability in glaucoma.⁷²^,⁷³ We have also recently shown that dLGN microglia respond to elevated IOP in DBA/2J mice and might take on a protective phenotype,⁴³ possibly supporting TC neuron compensatory responses. Overall, the cell-intrinsic or local mechanisms causing high IOP/glaucoma to trigger TC neuron compensatory responses remain to be determined.

Limitations of the study

The dLGN receives input from multiple RGC types and IOP differentially affects different RGCs. We have found considerable variability in many measured parameters, which could arise from differential effects depending on the RGC subtype innervating individual TC neurons, but we were unable to assess this possibility given the use of an extracellular optic tract stimulus. Additionally, while we used a standardized “physiological” stimulus train for driving retinogeniculate inputs, which was an essential control needed for make D2/D2-control comparisons, glaucoma can also alter RGC spiking properties,⁷² which means that RGC-level compensation might combine with the observed effects recorded at the level of the dLGN TC neurons to shape output to V1. Finally, we used the D2 mouse line in this study, which is widely used for rodent model for glaucoma research. While the mouse visual system follows the same general organization as in humans, there are several key differences including the relative fraction of RGC axons projecting to the thalamus vs. other non-thalamic targets. Moreover, although D2 glaucoma mimics certain features of human disease including age-dependent ocular hypertension and RGC loss, future work should expand to test whether the findings here are recapitulated in inducible rodent models and develop approaches for testing for similar phenomena in higher order animal models and human patient subjects.

Resource availability

Lead contact

Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Matthew Van Hook (matt.vanhook@unmc.edu).

Materials availability

This study did not generate new unique reagents.

Data and code availability

•
Data reported in this study are available in the supplemental Data and Statistics and can also be shared by the lead contact upon request.
•
RNA-sequencing data are publicly available, accessible at https://doi.org/10.1371/journal.pone.0323513.
•
This article does not report original code.
•
Any additional information required to reanalyze the data reported in this article is available from the lead contact upon request.

Acknowledgments

NIH R01 grant EY030507 (M.J.V.H.), Research to Prevent Blindness/The Glaucoma Foundation Career Advancement Award (M.J.V.H.), NIH T32 grant AG076407 (S.M.). We recognize the use of the University of Nebraska Medical Center – Tissue Science Facility, which receives support from the Buffett Cancer Center support grant P30CA03672. The graphical abstract was created in BioRender. Van Hook, M. (2026). https://BioRender.com/sf60h11.

Author contributions

Conceptualization, S.M. and M.J.V.H.; data curation, S.M., AJ, J.C.S., V.S., S.Y., G.P., and M.J.V.H.; formal analysis, S.M., A.J., J.C.S., V.S., S.Y., G.P., and M.J.V.H.; funding acquisition, M.J.V.H.; investigation, S.M., AJ, J.C.S., V.S., S.Y., G.P., and M.J.V.H.; methodology, S.M., J.C.S., S.Y., G.P., and M.J.V.H.; project administration, M.J.V.H.; supervision, M.J.V.H.; visualization, M.J.V.H. and S.M.; writing – original draft, S.M., A.J., and M.J.V.H.; writing – review and editing, S.M., J.C.S., and M.J.V.H.

Declaration of interests

The authors declare no competing interests.

STAR★Methods

Key resources table

REAGENT or RESOURCE	SOURCE	IDENTIFIER
Antibodies

Anti-ankyrin G, rabbit polyclonal	Synaptic Systems	Cat # 386 003; RRID:AB_2661876
Anti-rabbit, donkey IgG, Alexa Fluor 568	Invitrogen	Cat # A-10042; RRID:AB_2534017

Chemicals, peptides, and recombinant proteins

CNQX	Tocris	Cat # 0190
D-AP5	Tocris	Cat # 0106
SR95531	Tocris	Cat # 1262
DS2	Tocris	Cat # 3679
(S)-SNAP5114	Tocris	Cat # 1561

Deposited data

D2 and D2-control RNA sequencing dataset	Thompson et al., 2025⁴³	https://doi.org/10.1371/journal.pone.0323513.s002

Experimental models: Organisms/strains

DBA/2J mouse (“D2”)	The Jackson Laboratory	Strain: 000671; RRID:IMSR_JAX:000671
DBA/2J-Gpnmb⁺/SjJ (“D2-control”)	The Jackson Laboratory	Strain: 007048; RRID:IMSR_JAX:007048

Software and algorithms

ImageJ/FIJI	Fiji, https://fiji.sc	RRID:SCR_002285
Prism 10	GraphPad	RRID:SCR_002798
pClamp	Molecular Devices	RRID:SCR_011323

Open in a new tab

Experimental model and study participant details

All animal procedures were reviewed and approved by the Institutional Animal Care and Use Committee (IACUC, approval #18-131-10) at the University of Nebraska Medical Center. DBA/2J mice (D2, The Jackson Laboratory #000671, RRID:IMSR_JAX:000671) and DBA/2J-Gpnmb1⁺ mice (D2-control, The Jackson Laboratory #007048, RRID:IMSR_JAX:007048) were used for this study at 11-15 months of age, although most mice in this study were 11-13 months of age. When data sets for experiments included a range of ages, we tested whether there were differences between data from younger and older mice and pooled data if no differences were found. Mice of both sexes were used and we describe sex differences in the results section. The mice were bred and housed at the University of Nebraska Medical Center Comparative Medicine facilities on a 12h/12h light-dark cycle with free access to food and water. Intraocular eye pressure measurements (IOPs) were taken on D2 and D2-control eyes initially beginning at 3 - 5 months of age and subsequent IOPs were measured approximately monthly throughout the study.

Method details

Intraocular pressure measurements

IOPs were obtained using a TONOLAB rebound tonometer (iCare, Finland), displayed in mmHg. D2 and D2-control mice were lightly anesthetized with inhaled isoflurane (Piramal Critical Care, Bethlehem, PA). Mice were put in an induction chamber with approximately 4% isoflurane until sedated. Approximately 2% isoflurane, administered through a nose cone, was used to maintain sedation while six consecutive, low-error IOP measurements were taken from the central cornea to generate a single readout. Three readouts per eye were averaged to provide a single IOP value per eye for each time-point.

Pattern electroretinogram (pERG)

Mice were dark-adapted overnight prior to pERG recordings, which were performed using the Celeris Small Animal ERG system (Diagnosys LLC, Lowell MA USA). An intraperitoneal ketamine/xylazine injection [100 mg/kg ketamine (Zoetis, Parsipanny, NJ) and 5 mg/kg xylazine (Akorn Inc., Lake Forest, IL)] was used to anesthetize the mice, and tropicamide mydriatic eye drops (1%, Alcon Laboratories, Fort Worth, TX) and proparacaine topical anesthetic eye drops (0.5% Alcon Laboratories, Fort Worth, TX) were applied to each eye. Once the mouse was anesthetized, hypromellose gel (0.3%; GenTeal Tears, Alcon, Fort Worth, TX) was applied to the eyes, and an electrode/fiber optic stimulator was placed on one eye to serve as a reference electrode while a pattern stimulator/electrode was positioned on the other. The pattern stimulator was then used to deliver a 100% contrast reversing horizontal bar stimulus (0.059 cycles/degree, 50 cd/m², 2.1 Hz pattern reversal) while pERG waveforms were acquired at 2 kHz and bandpass filtered at 1-50 Hz. After acquiring pERG data from one eye, electrodes were switched, and pERG data were recorded from the other eye.

Slice preparation and electrophysiology

For preparation of slices for electrophysiology, the “protected recovery” method was used.¹⁰³^,¹⁰⁴ After mice were killed via CO₂ inhalation and cervical dislocation, brains were extracted and submerged in a slush of artificial cerebral spinal fluid (aCSF) for ∼1 min. The aCSF was comprised of the following: 128 mM NaCl, 2.5 mM KCl, 1.25 mM NaH₂PO₄, 24 mM NaHCO₃, 12.5 mM glucose, 2 mM CaCl₂, and 2 mM MgSO₄. For coronal slices containing dLGN, cerebellum was removed and the flat, exposed surface glued to the platform of a Leica VT1000S vibratome for slicing (250 micron thickness). For parasagittal slices containing optic tract and dLGN, the brain was hemisected ∼5 degrees from the medial longitudinal fissure and ∼20 degrees from the horizontal plane,¹⁰⁵^,¹⁰⁶ after which the medial surface was glued to the platform for slicing (300 micron thickness). After slicing, tissue was incubated for 12 minutes in a warmed (32°C) N-methyl-D-glucamine (NMDG) solution (92 mM NMDG, 2.5 mM KCl, 1.25 mM NaH₂PO₄, 25 mM glucose, 30 mM NaHCO₃, 20 mM HEPES, 0.5 mM CaCl₂, 10 mM MgSO₄, 2 mM thiourea, 5 mM L-ascorbic acid, and 3 mM Na-pyruvate and bubbled with 95% O₂ and 5% CO₂). Both the aCSF and NMDG solutions were prepared with a pH of 7.4 and osmolality of 300 – 315 mOsm. Slices were allowed to recover for at least 1 hour in room temperature aCSF (bubbled with 95% O₂/5% CO₂) prior to recording. Patch pipettes were pulled from thin-walled borosilicate glass with an internal filament and filled with either a Cs⁺- or K⁺-based pipette solution (Cs⁺-based solution: 120 mM Cs-methanesulfonate, 2 mM EGTA, 10 mM HEPES, 8 mM TEA-Cl, 5 mM ATP-Mg, 0.5 mM GTP-Na₂, 5 mM phosphocreatine-Na₂, 2 mM QX-314; K+-based solution: 120 mM K-gluconate, 8 mM KCl, 2 mM EGTA, 10 mM HEPES, 5 mM ATP-Mg, 0.5 mM GTP-Na₂, 5 mM phosphocreatine, pH = 7.4, 275 mOsm). Reported voltages are corrected for liquid junction potentials (10 mV for Cs⁺ and 14 mV for K⁺ pipette solutions). Electrophysiology data were acquired at 10 kHz with an Axon MultiClamp 700B amplifier and Digidata 1550 Digitizer (Molecular Devices). While recording, slices were superfused with aCSF (2 mL/minute) that was bubbled with 5% CO₂ / 95% O₂ and warmed to 30-33^oC with an in-line solution heater. Excitatory and inhibitory post-synaptic currents (EPSCs and IPSCs) evoked by optic tract stimulation were recorded while holding the TC neurons at -70 mV or -74 mV (for recording EPSCs with Cs⁺ or K⁺ pipette solutions, respectively) and 0 mV (for recording IPSCs), in response to stimulation of the optic tract using a aCSF-filled patch pipette (100-400 μA, 0.2 ms stimulus duration using an A-M Systems Isolated Pulse Stimulator) while synaptically-driven spiking was recorded in current clamp configuration. For recording locally-driven IPSCs,¹⁰⁷ an aCSF-filled patch pipette was positioned in the extracellular space approximately 25 microns from the recorded TC neuron in coronal slices and used to deliver a current stimulus (0.2-0.3 ms, 100-400 μA) in the presence of glutamatergic blockers (20 μM CNQX, 50 μM D-AP5). Intrinsic excitability was monitored in current clamp. A series of depolarizing current injections (500 ms duration) was used to measure the relationship of action potential firing to depolarizing current injection. For measuring rheobase, V_m was maintained at approximately –60 mV to inactivate LVA Ca²⁺ currents³² and a ramp current stimulus (500 pA amplitude, 2 pA/ms) was delivered. Rheobase was taken as the current stimulus at the threshold of the first action potential. To generate action potential phase plots and estimate membrane currents responsible for action potential generation, TC neurons were stably depolarized to –60 mV using a DC injection, and a short (2 ms) depolarizing current injection was used to evoke an action potential. Membrane capacitance was measured by integrating the whole-cell capacitance transient current over 10 ms in response to a –10 mV hyperpolarizing voltage step. Input resistance was measured in current clamp in response to a series of hyperpolarizing current injections. For constructing phase plots, the sampling frequency was increased to 100 kHz. For pharmacologically manipulating dLGN inhibition, we bath-applied DS2 (10 μM), a positive allosteric modulator of δ-subunit-containing GABA_A receptors, or the GABA transporter inhibitor SNAP5114 (60 μM), which disrupts GABA reuptake by astrocytes.

Immunofluorescence labeling

Brains were removed after mice were killed via CO₂ inhalation and cervical dislocation. For brains, tissue processing for histology began with a 4 hour fixation in 4% paraformaldehyde followed by 3 x 10 min washes in 1x PBS and cryo-protecting the brain in 30% sucrose in PBS overnight at 4^oC. Once cryo-protected, the brains were embedded in 3% agar in PBS. 50-μm-thick slices containing the dLGN were created using a Leica VT1000S vibratome, mounted on Superfrost Plus slides (Fisher), and stored at -20^oC until stained. The slides were rinsed in PBS followed by blocking and permeabilization for 1 hour in blocking buffer (PBS, 0.5% Triton X-100, 5.5% donkey serum, 5.5% goat serum, pH adjusted to 7.4 using NaOH). The slides were then incubated in primary antibody diluted in blocking buffer (1:1000 rabbit-anti-Ankyrin-G) for 3 nights at 4°C. Following incubation with primary antibodies, the slides were washed 6 x 10 min in PBS, incubated in blocking buffer for 1 hour, and incubated with secondary antibody diluted with blocking buffer (1:200 donkey anti-rabbit IgG, Alexa Fluor 568, Invitrogen A-10042). The slides were then washed 3 x 10 min in PBS and 1 x 1 min in dH₂O, coverslipped with Vectashield Hardset mounting medium, and stored at 4°C until imaged. Ankyrin-G was imaged on a Scientifica two-photon microscope with a MaiTai HP Ti-Sapphire laser tuned to 800 nm with a 123.33 x 123.33 μm field of view (8.303 pixels/μm) centered on the dLGN core. Four images per plane were acquired with 0.5 μm spacing between each plane (laser power at approximately 92 μW). Images were analyzed using ImageJ, where the images in each plane were grouped and averaged using the “grouped Z project” command with a projection method of “average intensity”. The “brightness/contrast” command was then applied with the “auto” setting to the images. The Simple Neurite Tracer plugin was then used to trace the axon initial segments in each image. The “straighten” command was then applied to each trace, and the intensity profile was plotted for each trace using the “plot profile” command.

Optic nerve histology

2-4 mm of optic nerve proximal to the globe was fixed in 4% paraformaldehyde for 3 hours, washed in PBS, and stained with a solution of 2% osmium tetroxide for two hours. Nerves were embedded in paraffin and cross sections obtained at 2 μm thickness by the UNMC Tissue Science Facility (RRID:SCR_012465). Cross sections were mounted on slides, stained with toluidine blue, and coverslipped with VectaShield Hardset. Whole cross sections of nerves were imaged on an Olympus BX51 WI microscope with a 10x objective (1.68 px/μm). For analyzing glial scarring of the optic nerves,²⁷ a region of interest was drawn around the nerve in ImageJ, local contrast was enhanced, and the image was sharpened. The image was thresholded to differentiate darkly-stained regions containing myelinated axons from unstained glial scar. The area of a binary mask comprised of the glial scar was measured and used to calculate the fractional glial scar area of the nerve cross section.

Quantification and statistical analysis

Statistical analysis was performed using GraphPad Prism 10. A D’Agostino-Pearson test was used to test the normality of data. If non-normally distributed, data were log-transformed prior to analysis or non-parametric approaches were used, as described in the Results. For analysis of Na⁺ and K⁺ channel expression, we examined a dLGN bulk RNA-sequencing dataset we previously published.⁴³ Z-scores were calculated with the log2-transformed FPKM values for each D2 and D2-control sample using the mean and standard deviation of the D2-control samples. For IOP measurements, a Mann-Whitney test was used to determine significance. A t-test was used to test for statistical significance of histological (glial scarring and axon initial segment length) and pERG data and for sex differences. For experiments involving multiple measurements from individual animals (i.e. patch clamp recordings from multiple cells and axon initial segment measurements), a nested t-test was used to avoid pitfalls from pseudoreplication.¹⁰⁸ Individual data points (cells, mice, eyes, nerves) along with mean±SEM (standard error of the mean), or median±IQR (inter-quartile range), as indicated in the figure legends. Figure legends indicate statistical significance, n.s., p>0.05; ∗p<0.05; ∗∗p<0.01; ∗∗∗p<0.005; ∗∗∗∗p<0.001.

Published: February 28, 2026

Footnotes

Supplemental information can be found online at https://doi.org/10.1016/j.isci.2026.115176.

Supplemental information

Document S1. Figures S1–S6

mmc1.pdf^{(433.2KB, pdf)}

Data S1. Excel file containing statistical tests and data, related to Figures 1, 2, 3, 4, 5 and 6

mmc2.xlsx^{(90.9KB, xlsx)}

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Document S1. Figures S1–S6

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Data S1. Excel file containing statistical tests and data, related to Figures 1, 2, 3, 4, 5 and 6

mmc2.xlsx^{(90.9KB, xlsx)}

Data Availability Statement

•
Data reported in this study are available in the supplemental Data and Statistics and can also be shared by the lead contact upon request.
•
RNA-sequencing data are publicly available, accessible at https://doi.org/10.1371/journal.pone.0323513.
•
This article does not report original code.
•
Any additional information required to reanalyze the data reported in this article is available from the lead contact upon request.

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PERMALINK

Compensatory responses to glaucoma pathology in the dorsolateral geniculate nucleus

Shaylah McCool

Arnav Jain

Jennie C Smith

Victoria Schaal

Gurudutt Pendyala

Sowmya Yelamanchili

Matthew J Van Hook

Summary

Graphical abstract

Highlights

Introduction

Results

Intraocular pressure and glaucoma pathology in DBA/2J mice

Figure 1.

Diminished retinogeniculate synapses drive robust action potential output in DBA/2J TC neurons

Figure 2.

Plasticity of intrinsic excitability in D2 mice

Figure 3.

Altered action potential generation mechanisms in D2 mice

Figure 4.

Feedforward inhibition is more transient in the DBA/2J dLGN

Figure 5.

Decreased activation of extrasynaptic GABAA receptors in DBA/2J TC neurons

Figure 6.

Discussion

Limitations of the study

Resource availability

Lead contact

Materials availability

Data and code availability

Acknowledgments

Author contributions

Declaration of interests

STAR★Methods

Key resources table

Experimental model and study participant details

Method details

Intraocular pressure measurements

Pattern electroretinogram (pERG)

Slice preparation and electrophysiology

Immunofluorescence labeling

Optic nerve histology

Quantification and statistical analysis

Footnotes

Supplemental information

References

Associated Data

Supplementary Materials

Data Availability Statement

ACTIONS

PERMALINK

RESOURCES

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Links to NCBI Databases

Decreased activation of extrasynaptic GABA_A receptors in DBA/2J TC neurons