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. 2019 Mar 7;176(6):1393–1406.e16. doi: 10.1016/j.cell.2018.12.037

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© 2019 The Authors

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

PMC Copyright notice

dCA1 Axons Drive Both MSN and PV⁺FSI Postsynaptic Responses and Exert Feedforward Inhibition on dCA1-Connected MSNs

(A) dCA1 PYRs were transduced with CamKII-ChR2-eYFP and NAc PV⁺ interneurons were visualized by the tdTomato fluorescent reporter in PV-Cre mice. Whole-cell patch-clamp recordings of NAc FSIs and MSNs were performed in combination with blue light wide-field NAc optogenetic stimulation of dCA1 ChR2-eYFP axons (2- to 3-ms duration light ON^NAc pulses).

(B) Whole-cell patch-clamp configuration. Top: Dodt contrast image of simultaneously recorded NAc FSI and MSN and corresponding current-voltage plots highlighting the responses to depolarizing current steps. Bottom: corresponding fluorescence image with simultaneously recorded tdTomato-expressing PV⁺FSI and unlabeled MSN.

(C) The neurons recorded in (B) and labeled with biocytin (top left), with the presence of dCA1 ChR2-eYFP axons (top right). The tdTomato-expressing FSI (bottom left) is PV-immunopositive (bottom right).

(D) Example EPSPs evoked in an MSN and PV⁺FSI in response to optogenetic stimulation of dCA1 axons. Note the larger EPSP in the PV⁺FSI.

(E and F) Optogenetic stimulation of dCA1 axons evoked significantly larger EPSPs (E) in PV⁺FSIs with shorter rise times (F). One off-display PV⁺FSI data point (E, 1.46 mV). A total of 8 of 16 PV cells and 13 of 25 MSNs exhibited an EPSP response to activation of dCA1 axons. None of the neighboring PV-negative interneurons responded to photo-stimulation of dCA1 inputs (n = 6).

(G) PV⁺FSIs exhibited less paired-pulse depression than MSNs following successive photo-stimulations of dCA1 axons (paired-pulse ratio: n = 5 PV⁺FSIs and 15 MSNs; with EPSP amplitude: PV⁺FSIs = 0.79 ± 0.18mV, MSN = 0.22 ± 0.04 mV, p = 0.01, Wilcoxon test, n = 5 cell-pair recordings, where both PV⁺FSIs and MSN cells received dCA1 inputs). Example traces for one MSN and one PV⁺FSI recorded during paired-pulse stimulations of dCA1 axons shown on top.

(H) Stimulation of dCA1 axons with increased light intensity resulted in action potential discharges by a PV⁺ FSI, but not by a simultaneously recorded MSN.

(I) Resting membrane voltage for recorded PV⁺FSIs and MSNs. PV⁺FSIs were significantly more depolarized than MSNs.

(J) Input resistance was significantly higher in PV⁺FSIs compared to MSNs. We did not observe significant differences in the electrophysiological properties of FSIs and MSNs that did or did not respond to dCA1 axon stimulation (Table S1).

(K and L) dCA1 axon stimulation elicited both EPSCs and IPSCs in dCA1-connected MSNs. Voltage-clamp recordings were performed for MSNs that showed dCA1-evoked EPSPs under current-clamp (n = 8 dCA1-responding MSNs of 18 tested MSNs; all dCA1-responding MSNs exhibited both EPSCs and IPSCs; E/I ratio = 1.58 ± 0.45). IPSCs and EPSCs recorded by holding MSNs at 0 mV and −75 mV, respectively. Shown in (K) are average IPSC (top) and EPSC (bottom) traces for one MSN (20 sweeps of 473nm dCA1 axon stimulation). Peak amplitude of recorded EPSCs and IPSCs shown in (L) (with off-display pair of data points for one MSN: EPSC = 134.80 pA, IPSC = 98.04 pA). Note that all recorded dCA1-responding MSNs received both excitatory and inhibitory currents upon dCA1 input stimulation.

^∗∗p < 0.01, ^∗∗∗p < 0.001, Mann-Whitney U test.

See also Table S1.