Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity

Jinxu Liu, Gajanan P. Shelkar, Pauravi J. Gandhi, Dinesh Y. Gawande, Andrew Hoover, Rosa M. Villalba, Ratnamala Pavuluri, Yoland Smith, Shashank M. Dravid

Research output: Contribution to journalArticle

Abstract

Impaired behavioral flexibility and repetitive behavior is a common phenotype in autism and other neuropsychiatric disorders, but the underlying synaptic mechanisms are poorly understood. The trans-synaptic glutamate delta (GluD)-Cerebellin 1-Neurexin complex, critical for synapse formation/maintenance, represents a vulnerable axis for neuropsychiatric diseases. We have previously found that GluD1 deletion results in reversal learning deficit and repetitive behavior. In this study, we show that selective ablation of GluD1 from the dorsal striatum impairs behavioral flexibility in a water T-maze task. We further found that striatal GluD1 is preferentially found in dendritic shafts, and more frequently associated with thalamic than cortical glutamatergic terminals suggesting localization to projections from the thalamic parafascicular nucleus (Pf). Conditional deletion of GluD1 from the striatum led to a selective loss of thalamic, but not cortical, terminals, and reduced glutamatergic neurotransmission. Optogenetic studies demonstrated functional changes at thalamostriatal synapses from the Pf, but no effect on the corticostriatal system, upon ablation of GluD1 in the dorsal striatum. These studies suggest a novel molecular mechanism by which genetic variations associated with neuropsychiatric disorders may impair behavioral flexibility, and reveal a unique principle by which GluD1 subunit regulates forebrain circuits.

Original languageEnglish (US)
Article number104746
JournalNeurobiology of Disease
Volume137
DOIs
StatePublished - Apr 2020

All Science Journal Classification (ASJC) codes

  • Neurology

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    Liu, J., Shelkar, G. P., Gandhi, P. J., Gawande, D. Y., Hoover, A., Villalba, R. M., Pavuluri, R., Smith, Y., & Dravid, S. M. (2020). Striatal glutamate delta-1 receptor regulates behavioral flexibility and thalamostriatal connectivity. Neurobiology of Disease, 137, [104746]. https://doi.org/10.1016/j.nbd.2020.104746