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Glutamate Delta-1 Receptor Regulates Inhibitory Neurotransmission in the Nucleus Accumbens Core and Anxiety-Like Behaviors

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Abstract

Glutamate delta-1 receptor (GluD1) is a member of the ionotropic glutamate receptor family expressed at excitatory synapses and functions as a synaptogenic protein by interacting with presynaptic neurexin. We have previously shown that GluD1 plays a role in the maintenance of excitatory synapses in a region-specific manner. Loss of GluD1 leads to reduced excitatory neurotransmission in medium spiny neurons (MSNs) in the dorsal striatum, but not in the ventral striatum (both core and shell of the nucleus accumbens (NAc)). Here, we found that GluD1 loss leads to reduced inhibitory neurotransmission in MSNs of the NAc core as evidenced by a reduction in the miniature inhibitory postsynaptic current frequency and amplitude. Presynaptic effect of GluD1 loss was further supported by an increase in paired pulse ratio of evoked inhibitory responses indicating reduced release probability. Furthermore, analysis of GAD67 puncta indicated a reduction in the number of putative inhibitory terminals. The changes in mIPSC were independent of cannabinoid or dopamine signaling. A role of feed-forward inhibition was tested by selective ablation of GluD1 from PV neurons which produced modest reduction in mIPSCs. Behaviorally, local ablation of GluD1 from NAc led to hypolocomotion and affected anxiety- and depression-like behaviors. When GluD1 was ablated from the dorsal striatum, several behavioral phenotypes were altered in opposite manner compared to GluD1 ablation from NAc. Our findings demonstrate that GluD1 regulates inhibitory neurotransmission in the NAc by a combination of pre- and postsynaptic mechanisms which is critical for motor control and behaviors relevant to neuropsychiatric disorders.

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Data is available from the corresponding author upon reasonable request.

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Funding

This work was supported by grants from the NSF1456818 (SMD), NIH NS104705 (SMD), NIH NS118731 (SMD) and NIH MH116003 (SMD). DC was supported by NIH training grant T32-GM008602.

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Author notes

  1. Dinesh Y. Gawande, Gajanan P. Shelkar and Jinxu Liu are contributed equally to this work

Authors and Affiliations

  1. Department of Pharmacology and Neuroscience, Creighton University, 2500 California Plaza, Omaha, NE, USA

    Dinesh Y. Gawande, Gajanan P. Shelkar, Jinxu Liu, Anna D. Ayala, Ratnamala Pavuluri & Shashank M. Dravid

  2. Yerkes National Primate Research Center, Atlanta, GA, 30329, USA

    Diane Choi & Yoland Smith

  3. UDALL Center of Excellence for Parkinson’s Disease, Atlanta, GA, 30329, USA

    Diane Choi & Yoland Smith

  4. Department of Neurology, Emory University, Atlanta, GA, 30329, USA

    Yoland Smith

Authors
  1. Dinesh Y. Gawande
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  2. Gajanan P. Shelkar
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Contributions

DYG, GPS, JL, AA, RP, DC, YS, SMD conducted experiments, contributed to writing the manuscript and/or analyzed data. All authors contributed to research design and reviewed the final manuscript.

Corresponding author

Correspondence to Shashank M. Dravid.

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All animal studies were approved by Creighton University, Institutional Animal Care and Use Committee.

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Supplementary Information

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Supplementary Figure 1.

Expression of GluD1 in somatostatin neurons in the NAc core. Immunohistochemical studies were conducted with double labeling for somatostatin (SOM, red) and GluD1 (green). Confocal imaging in the NAc core demonstrate the localization of GluD1 puncta onto SOM neurons (arrows in overlay). (PDF 494 KB)

Supplementary Figure 2.

Effect of conditional ablation of GluD1 from PV neurons on sensorimotor function.(A) PV-Cre (N = 8) and PV-GluD1 KO (N = 9) mice did not show any significant change in PPI (for 74: PV-Cre 47.53 ± 5.941 vs PV-GluD1 KO 39.05 ± 7.124 p = 0.3824; for 78: PV-Cre 63.82 ± 2.528 vs PV-GluD1 KO 59.3 ± 5.526 p = 0.4868; for 84: PV-Cre 78.84 ± 3.631 vs PV-GluD1 KO 73.61 ± 4.546 p = 0.3912, unpaired t-test). (A’) No change in startle amplitude was found in PV-GluD1 KO mice compared to the PV-Cre mice (PV-Cre 411.4 ± 76.59 vs PV-GluD1 KO 509.9 ± 56.33 p = 0.3097, unpaired t-test). (B) PV-Cre (N = 8) and PV-GluD1 KO (N = 9) mice were tested for motor coordination and learning in rotarod test. No significant deficit in motor coordination and learning was observed between the genotypes. (C) Pre- (basal) and post-MK-801 induced locomotor activity for each genotype is depicted. After MK-801 administration a significant change in total locomotor activity was observed in PV-GluD1 KO (PV-Cre 221.6 ± 18.88 vs PV-GluD1 KO 307.2 ± 24.61 p=0.0493, unpaired t-test) mice compared to the PV-Cre mice. (C’) Locomotor activity in 5 min segment for 60 minutes post-MK-801 injection was plotted and compared. PV-GluD1 KO (N = 4) showed significant increase (at 65 min: PV-Cre 24.042 ± 2.420 vs PV-GluD1 KO 36.460 ± 1.553 p=0.0282, Two-way ANOVA; Bonferonni post-hoc test) in locomotor activity following MK-801 treatment compared to PV-Cre (N = 3) mice. (PDF 57 KB)

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Gawande, D.Y., Shelkar, G.P., Liu, J. et al. Glutamate Delta-1 Receptor Regulates Inhibitory Neurotransmission in the Nucleus Accumbens Core and Anxiety-Like Behaviors. Mol Neurobiol 58, 4787–4801 (2021). https://doi.org/10.1007/s12035-021-02461-3

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