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. Author manuscript; available in PMC: 2022 Oct 15.
Published in final edited form as: Neurosci Lett. 2021 Aug 17;763:136180. doi: 10.1016/j.neulet.2021.136180

Rescue of BDNF Expression by the Thalamic Parafascicular Nucleus with Chronic Treatment with the mGluR2/3 Agonist LY379268 may Contribute to the LY379268 Rescue of Enkephalinergic Striatal Projection Neurons in R6/2 Huntington’s Disease Mice

H Wang 1, N Del Mar 1, Y Deng 1, A Reiner 1,2
PMCID: PMC8440436  NIHMSID: NIHMS1736244  PMID: 34416343

Abstract

We have found that daily subcutaneous injection with a maximum tolerated dose of the mGluR2/3 agonist LY379268 (20 mg/kg) beginning at 4 weeks of age dramatically improves the motor, neuronal and neurochemical phenotype in R6/2 mice, a rapidly progressing transgenic model of Huntington’s disease (HD). We also previously showed that the benefit of daily LY379268 in R6/2 mice was associated with increases in corticostriatal brain-derived neurotrophic factor (BDNF), and in particular was associated with a reduction in enkephalinergic striatal projection neuron loss. In the present study, we show that daily LY379268 also rescues expression of BDNF by neurons of the thalamic parafascicular nucleus in R6/2 mice, which projects prominently to the striatum, and this increase too is linked to the rescue of enkephalinergic striatal neurons. Thus, LY379268 may protect enkephalinergic striatal projection neurons from loss by boosting BDNF production and delivery via both the corticostriatal and thalamostriatal projection systems. These results suggest that chronic treatment with mGluR2/3 agonists may represent an approach for slowing enkephalinergic neuron loss in HD, and perhaps progression in general.

Keywords: Huntington’s Disease, Therapy, mGluR2/3, Striatum, BDNF

Introduction

We have found that daily subcutaneous injection with a maximum tolerated dose (MTD) of the Group II metabotropic glutamate receptor agonist LY379268 (20mg/kg), which targets metabotropic glutamate receptor 2 (GluR2) and metabotropic glutamate receptor 3 (mGluR3), beginning at 4 weeks of age, dramatically improves the phenotype in R6/2 mice, a transgenic model of Huntington’s disease (HD) (1). For example, this regimen prevents a 15–20% striatal neuron loss and severe motor impairment otherwise seen at 10 weeks of age in R6/2 mice. A prior study of ours showed that the benefit of daily LY379268 in R6/2 mice was associated with significant restoration of BDNF production by corticostriatal neurons, which was correlated with the improved survival of enkephalinergic indirect pathway type striatal projection neurons (2). These findings are consistent with the evidence that cortical BDNF production and delivery to striatum is substantially reduced in human HD and in transgenic HD mice (3, 4, 5), that such diminished cortical production of BDNF harms striatum (6, 7, 8), and that intrastriatal BDNF delivery or selective forebrain overexpression of BDNF reverse cortical and striatal pathology and improve motor performance in transgenic HD mice (7, 9, 10, 11). The thalamostriatal neurons of the parafascicular nucleus (PFN), however, also produce BDNF, have a substantial projection to striatum (12, 13), and together with the dopaminergic nigrostriatal neurons of the substantia nigra pars compacta (SNc) account for about 35% of striatal BDNF (6, 14, 15). As BDNF expression in PFN neurons is progressively reduced in R6/2 mice (15) and PFN neurons undergo degeneration during the course of HD (16), the resulting reduction in thalamostriatal BDNF may contribute to HD pathogenesis. In the present study, we used in situ hybridization histochemistry (ISHH) to examine BDNF expression in PFN in 10-week old R6/2 mice (to confirm its reduction), and determined if chronic LY379268 treatment reversed any observed deficit in BDNF expression by PFN. We focused on PFN because its contribution to striatal BDNF appears greater than that of SNc (14, 15, 17), and because of its substantial input to striatal projection neurons relative to the cortical input (12, 13). We found that BDNF expression in PFN was, in fact, significantly reduced in R6/2 mice at 10-weeks of age. Moreover, we observed that daily LY379268 treatment via subcutaneous injection significantly improves parafascicular BDNF expression and this improvement appeared to contribute to the rescue of enkephalinergic (ENK+) striatal projection neurons seen with daily LY379268 in R6/2 mice (2). These results further support the view that chronic treatment with mGluR2/3 agonists may represent an approach for slowing HD progression.

Material and Methods

R6/2 mice were used in this study because they replicate the preferential enkephalinergic striatal projection neuron vulnerability of human HD, and because their rapid progression provides a useful initial screen of therapy benefit (1, 2). R6/2 mice were maintained from founders obtained from JAX (strain # 006494) (Bar Harbor, ME), by breeding R6/2 mice with CBA × C57BL/6 F1 (B6CBAF1) mice. Genotype and CAG repeat length were determined by PCR-based amplification using genomic DNA extracted from tail biopsies and carried out by the Laragen Corporation (Culver City, CA). Mice received either 20 mg/kg LY379268 or vehicle (physiological saline) daily at about noon by subcutaneous (sc) injection on their rump, beginning during the fourth week of life after genotyping and group assignment. Both R6/2 mutant and WT littermate males and females treated with vehicle (WTV and R62V) or LY379268 (WTLY and R62LY) were studied by ISHH assessment of perikaryal BDNF levels in PFN in vehicle-treated mice, and of LY379268 efficacy in increasing expression of BDNF in PFN neurons and mitigating loss of striatal ENK+ neurons in R6/2 mice. Brain tissue sections from 53 mice that had been used in Reiner et al., 2012 (2), plus 38 additional mice, were used here for the PFN analysis. Details on animal numbers per treatment group are provided in the Results section. Males and females were used in largely equal numbers per group, and results did not differ notably between males and females. Repeat length was 126.6 CAG for mutants, and did not differ between vehicle- or LY379268-treated R6/2 mice, or males and females. BDNF data for perikarya in layer 5 of primary (M1) motor cortex and data on striatal ENK+ neuron abundance from our prior study (2) are used here again for assessing the contribution of thalamic PFN expression of BDNF to the LY379268 benefit for enkephalinergic striatal neuron survival relative to the role of corticostriatal BDNF. Based on our prior findings (1, 2), it is likely that the reduced numbers of ENK+ striatal neurons we observe in R6/2 mice at 10-weeks of age represents true neuron loss, and not merely loss of ENK expression in otherwise surviving neurons.

In situ Hybridization Histochemistry Studies.

We analyzed tissue from vehicle-treated and MTD LY379268-treated 10-week old R6/2 and WT mice (treated daily since the fourth week of life) that had been fresh-frozen processed for ENK and BDNF mRNA detection by ISSH, using previously described methods (1, 2, 18). ISHH was performed on 20 μm thick fresh-frozen cryostat sections through the PFN. The sections were collected onto pre-cleaned Superfrost®/Plus microscope slides, dried on a slide warmer, and stored at −80°C until used for ISHH. To process sections for ISHH, the slides were removed from −80°C, quickly thawed and dried using a hair dryer. After fixation with 2% paraformaldehyde in saline sodium citrate (2x SSC) for 5 minutes, the sections were acetylated with 0.25% acetic anhydride/0.1M triethanolamine hydrochloride (pH 8.0) for 10 minutes, dehydrated through a graded ethanol series, and air-dried. Digoxigenin-UTP labeled cRNA probes (i.e. riboprobes) for preproenkephalin (PPE) were transcribed from plasmids with PPE cDNA inserts (817bp in size), generated by us using RT-PCR. Primers for PPE PCR were: Sense: 5’-TTCCTGAGGCTTTGCACC-3’, and Antisense: 5’-TCACTGCTGGAAAAGGGC-3’. Primers for BDNF PCR were: Sense: 5’-GGCGCCCATGAAAGAAGTAAAC-3’, and Antisense: 5’-CGGCAACAAACCACAACATTAT-3’. The PPE riboprobe was directed against nucleotides 312–1128 (GenBank accession number NM_001002927), while the BDNF riboprobe was directed against nucleotides 715–1634 (GenBank accession number MN_007540), which includes the protein coding region of BDNF and part of the adjacent 3-prime untranslated sequence. Note that all BDNF transcripts share this sequence, found within exon IX of the BDNF gene, and thus our probe detected all BDNF transcripts. The sections were incubated with digoxigenin (DIG)-labeled probe in hybridization buffer containing 50% formamide, 4x SSC, 1x Denhardt’s solution, 200μg/ml denatured salmon sperm DNA, 250μg/ml yeast tRNA, 10% dextran sulfate, and 20mM dithiothreitol (DTT) at 63°C overnight. After hybridization, the slices were washed at 58°C consecutively in 4x SSC, 50% formamide with 4x SSC, 50% formamide with 2x SSC, and then 2x SSC, followed by treatment with RNase A (20μg/ml) for 30 min at 37°C. Finally, sections were washed at 55°C in 1xSSC, 0.5xSSC, 0.25xSSC, dehydrated through a graded ethanol series, and air-dried. Digoxigenin labeling was detected using anti-digoxigenin Fab fragments conjugated to alkaline phosphatase, as visualized with nitroblue tetrazolium histochemistry (Roche, Indianapolis, IN).

Analysis of ISHH Labeling.

Blinded counts of BDNF+ perikarya were performed bilaterally on high-resolution images of PFN from one section from each animal, which were captured using a high-resolution Aperio Scanscope XT Scanner. Neuron abundance reported here for BDNF represents the labeled neuron number per mm2 for the mid-level of PFN where it surrounds the fasciculus retroflexus. Relative BDNF message was calculated as the product of the area of PFN containing BDNF-labeled neurons and the mean signal intensity of the PFN area containing BDNF-labeled neurons (as measured by ImageJ). Images were standardized to a common background intensity for these measurements, using fasciculus retroflexus for PFN and external capsule for cerebral cortex. Levene’s test was used to confirm homogeneity of variance. The values for the two sides of the brain for each mouse were averaged. Group results were analyzed by ANOVA using SPSS, with Fisher PLSD used for individual group comparisons. Linear regression was used to assess the relationship between PFN and/or M1 motor cortex layer 5 perikaryal BDNF signal on one hand and striatal ENK+ neuron abundance on the other, using M1 BDNF expression data and ENK+ striatal neuron counts for these same mice from our previously published study on corticostriatal BDNF (2). Missing data was mean filled for 8 mice for which we did not have all three values for the regression analysis, which was also performed using SPSS.

Results

We observed that BDNF expression was prominent in PFN neurons in WT mice, but reduced in vehicle-treated R6/2 mice (Fig. 1). Our measurements revealed that relative perikaryal BDNF message signal magnitude in PFN in vehicle-treated R6/2 mice (n=22) was 64.0% of that in vehicle-treated WT mice (n=21), which was significantly less (p<0.0110) than in the vehicle-treated WT mice. Perikaryal BDNF message in PFN was elevated by daily LY379268 treatment of R6/2 mice (n=23) to 79.6% of vehicle-treated WT mice (Fig. 2), which was no longer significantly different than in vehicle-treated WT mice (p=0.1396), indicating a partial rescue effect of LY379268 treatment. LY379268 treatment did not significantly affect BDNF message in PFN in WT mice (n=22). We did not detect any significant loss in the numbers of BDNF+ neurons in PFN per unit area (i.e. spatial density) in the vehicle-treated R6/2 mice (although their spatial density was lessened by about 10%), nor was the abundance of BDNF+ neurons in PFN per unit area elevated by LY379268 treatment in R6/2 mice (Fig. 2). Thus, LY379268 treatment boosted BDNF message in PFN neurons closer to normal levels, but did not demonstrably affect BDNF+ PFN neuron numbers at 10 weeks of age, which was not significantly reduced per unit area in any case in the R62V mice.

Figure 1.

Figure 1.

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Images of right parafascicular nucleus (PFN), showing ISHH labeling for BDNF message, in 10-week old WT mice injected sc daily with either vehicle (WTV) or LY379268 (WTLY) compared to 10-week old R6/2 mice injected sc daily with either vehicle (R62V) or LY379268 (R62LY). Note that BDNF message is reduced in the R6/2 mice, and increased by LY379268 in R6/2 mice. Images A-D are to the same scale, and scale bar in C applies to all four. FR = fasciculus retroflexus.

Figure 2.

Figure 2.

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Effect of LY379268 on BDNF message in the parafascicular nucleus and BDNF+ neuron spatial density (perikaryal per unit area), at 10 weeks of age. Perikaryal BDNF signal level differed between groups, but BDNF+ neuron abundance per unit PFN area did not. In particular, R6/2 mice receiving vehicle (R62V) showed significantly lower BDNF message in PFN than did WT mice receiving either vehicle (WTV) or LY379268 (WTLY) (asterisk), but R6/2 mice treated with LY379268 did not. BDNF neuron spatial density, however, was not significantly reduced in PFN in R6/2 mice. Mice used for PFN BDNF+ neuron counts: 10 WTV, 10 WTLY, 9 R62V, and 9 R62LY. Mice used for BDNF expression in PFN: 21 WTV, 22 WTLY, 22 R62V, and 23 R62LY. The results are shown as bar graphs with individual data point superimposed.

We previously reported that the abundance of enkephalinergic (ENK+) neurons in striatum of vehicle-treated 10-week old R6/2 mice is significantly reduced to about 70% of that in vehicle-treated WT mice, and significantly increased but not fully normalized by daily LY379268 treatment (2). Across the four groups and 53 mice used for this analysis, the abundance of enkephalinergic striatal neurons was highly and significantly correlated (r=0.53415) with the level of M1 cortical layer 5 perikaryal BDNF message (p=0.00038), the latter of which was reduced to 47.1% of WTV in R62V mice (p=0.0001) and restored to 78.9% of WTV in R62LY mice (a significant increase compared to R62V mice, p=0.00367). The PFN perikaryal BDNF signal was also significantly correlated with the abundance of ENK+ striatal neurons (p=0.043473), but the correlation was lesser (r=0.27848) than for M1 layer 5 neurons. Although both correlations are significant, the higher correlation for M1 suggests a greater impact of cortical M1 BDNF message loss on ENK+ striatal neuron loss than of PFN BDNF message loss, in keeping with the greater contribution of cortex to striatal BDNF (6, 14), and the greater cortical than thalamic BDNF loss in R6/2 mice observed here. Nonetheless, using multivariate regression analysis to assess the combined impact of PFN expression and cortical expression of BDNF, we found that together they were more highly (r=0.57166) and significantly (p=0.000051) correlated with enkephalinergic striatal neuron abundance than was either alone. Thus, the BDNF boost by LY379268 for cortex and PFN both appear to contribute to ENK+ striatal neuron survival, although the former more so. Note, however, this interpretation assumes that BDNF production is largely linear with BDNF message.

Discussion

Brain-derived neurotrophic factor (BDNF) is produced by cortical and thalamic neurons and transported axonally to their projection targets, including striatum (5, 6, 15), where it promotes the development, differentiation, plasticity and survival of neurons (5, 19, 20). As shown in the present and prior studies, mutant huntingtin reduces cortical and thalamic BDNF expression and protein transport to striatum in HD mice (2, 3, 4, 5, 15). Various lines of evidence indicate this may play a role in striatal pathogenesis and dysfunction in HD, particularly for enkephalinergic indirect pathway striatal projection neurons (3, 4, 5, 6, 7, 8). For example, placing the R6/1 HD transgene on a hemizygous BDNF knock-out background exacerbates striatal ENK+ neuron loss but does not affect the survival of direct pathway substance P-containing (SP+) striatal projection neurons (7). Moreover, cortex-specific BDNF knock-out results in striatal pathology that mimics that in human HD, including the greater ENK+ neuron vulnerability (6, 8), and embryonic deletion of the BDNF receptor (TrkB) from striatal neurons results in a particularly profound reduction in ENK+ striatal neurons (21). Note that the fact that cortex-specific BDNF knock-out does not yield as rapidly a progressive striatal pathology as seen in R6/2 mice (1, 2, 6) indicates that additional mechanisms beyond disrupted delivery of BDNF to striatum by the corticostriatal projection contribute to R6/2 pathogenesis. It may be that diminished thalamostriatal delivery of BDNF is one of these additional factors driving more rapid pathogenesis in R6/2 mice.

The above lines of evidence suggest that boosting striatal BDNF might be therapeutic in HD. Consistent with this conclusion, behavioral performance is improved and disease progression is slowed in transgenic HD mice overexpressing BDNF (9, 11). Similarly, daily intrastriatal administration of BDNF in R6/1 HD mice increases the number of striatal neurons expressing ENK and improves behavior (7), and driving expression of BDNF in striatal astrocytes delays the R6/2 motor phenotype (10, 22). Similarly, striatal BDNF infusion (23) or driving BDNF expression with daily doxycycline (24) mitigates disease in R6/2 mice. Note that the HD mutation also reduces striatal levels of the BDNF receptor TrkB (25, 26), which in principle might render increasing BDNF levels not fully effective in restoring pro-survival BNDF signaling in striatal neurons. Our unpublished qPCR data indicate, however, that the beneficial actions of LY379268 in R6/2 mice also involve increasing striatal TrkB levels, thus mitigating this concern for LY379268 at least. In addition to its action in boosting BDNF signaling in striatum, chronic LY379268 treatment may also be beneficial for striatal neurons in HD by means of its demonstrated anti-excitotoxic actions. Excitotoxicity mediated by corticostriatal release of glutamate, made harmful by either excessive release or excessive postsynaptic activation of extrasynaptic NMDA receptors, has also been proposed to be involved in HD pathogenesis (27, 28), and may also be among the additional processes that make R6/2 pathogenesis more rapid than seemingly could be achieved by cortical knockout of BDNF expression alone (1, 2, 6). Corticostriatal and thalamostriatal terminals are enriched in mGluR2/3, which are negative coupled to adenylyl cyclase (29) and thereby act as autoreceptors that dampen glutamate release (30, 31, 32). An mGluR2/3 agonist such as LY379268 reduces glutamate release and thereby reduces activation of extrasynaptic NMDA-type glutamate receptors, which are thought to underlie excitotoxic injury to striatal neurons in HD (27, 33). In our prior study, we showed that SP+ striatal neurons in R6/2 mice do not show an evident BDNF dependence in WT mice or R6/2 mice at 10-weeks of age (2), suggesting that their eventual loss in HD (34, 35) is not driven notably by BDNF deprivation. It may be their loss is driven more by excitotoxicity, potentially explaining why the two main striatal projection neuron types show differential vulnerability in HD – they are largely injured by different pathogenic processes. In any case, as mGluR2/3 agonists such as LY379268 are apparently neuroprotective by both their BDNF boosting effects and their anti-excitotoxic actions (32), they may effectively protect both projection neuron types over the course of disease. The means by which both acute and chronic LY379268 increases BDNF production by corticostriatal and thalamostriatal neurons (2, 36) is uncertain, but activation of extrasynaptic NMDA receptors on BDNF-producing cortical neurons is known to inhibit their BDNF expression (37). Thus, increased extrasynaptic NMDA receptor activation among cortical and thalamic neurons in HD brain may hinder their BDNF production, and attenuation of extrasynaptic NMDA receptor signaling by mGluR2/3 agonists such as LY379268 may thus reverse this.

Our prior study showing that daily LY379268 treatment boosts BDNF message in corticostriatal neurons and in R6/2 striatum (2) and the present evidence that daily LY379268 treatment also boosts BDNF message in PFN thalamostriatal neurons and contributes to neuroprotection of striatal enkephalinergic neurons is of interest with regard to therapeutic approaches for HD, given our findings that daily LY379268 treatment also ameliorates other HD-like neuropathology and motor deficits in R6/2 mice, and may also have a neuroprotective anti-excitotoxic action (1, 2). Although a variety of approaches have been tested and shown efficacy in reducing symptoms in mutant HD mice (38, 39), therapies that have been subsequently tested in human clinical trials have not had success in slowing HD in human patients. For example, although inhibition of phosphodiesterase 10A (PDE10A) with the compounds PF-04898798 or PF-02545920 was reported to reduce HD symptoms in mouse models (40), a clinical trial with PF-02545920 in HD patients failed to show efficacy (41). Similarly, knockdown of mutant (and wild-type) huntingtin expression by delivery into the nervous system of antisense oligonucleotides against huntingtin message was extensively and successfully tested in animal models (42), but nonetheless intrathecal delivery in human clinical trials of some of these same constructs proved ineffective (43). The encouraging results we have obtained here and in our prior studies (1,2) with the mGluR2/3 agonist LY379268 in abating motor deficits and reversing brain abnormalities in R6/2 mice, a highly aggressive model of HD, and in combating the presumed underlying pathogenic mechanisms, suggests that perhaps this class of drug should be given more consideration as a straightforward pharmacological approach for slowing HD progression. In this regard, it would be useful to test mGluR2/3 agonist benefit in additional animal models that more precisely mimic human HD genetically.

Acknowledgments

We thank Aminah Henderson, Marion Joni, and Ting Wong for histological assistance, and Michael Piantedosi and Trevon Clark for assistance with behavioral studies and mouse colony maintenance.

Funding

Supported by the CHDIF (AR), and NIH NS28721 (AR). The authors have no financial interest in the research reported here.

Abbreviations:

BDNF

brain-derived neurotrophic factor

ENK

enkephalin

FR

fasciculus retroflexus

HD

Huntington’s disease

ISHH

in situ hybridization histochemistry

GluR2

metabotropic glutamate receptor 2

mGluR3

metabotropic glutamate receptor 3

mGluR2/3

type II metabotropic glutamate receptors

MTD

maximum tolerated dose

PFN

parafascicular nucleus

R62V

Vehicle-treated R6/2 mice

R62LY

LY379268-treated R6/2 mice

sc

subcutaneous

SNc

substantia nigra pars compacta

SP

substance P

TrkB

BDNF receptor

WT

wild-type

WTV

vehicle-treated WT mice

WTLY

LY379268-treated WT mice

Footnotes

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Declaration of Interest: None.

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