# Function of glutamate delta-1 receptor

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2022 · $162,849

## Abstract

Summary:
 The delta family of ionotropic glutamate receptors consisting of glutamate delta 1 (GluD1) and glutamate delta 2
(GluD2) are unusual since they do not exhibit typical ligand-gated ionic currents. Instead, they are endowed with
synaptogenic property by forming a trans-synaptic GluD-Cerebellin1 (Cbln1)-Neurexin complex and inducing synapse
formation. In addition, the GluD receptors have C-terminal interactions which may stabilize postsynaptic density
machinery and contribute to synaptic plasticity. Although the function of GluD2 subunit in the formation and plasticity of
parallel fiber-Purkinje cell synapse in the cerebellum is well established the role of GluD1 enriched in the forebrain
remains largely unknown. This has important implications for our understanding of neurodevelopmental and
schizoaffective disorders since GRID1 gene that codes for GluD1 is strongly associated with autism, schizophrenia,
bipolar disorder and major depression. In addition, Neurexin1 is also highly associated with mental disorders and both
Cbln1 and Neurexin1 splice variant levels change in an activity-dependent manner and are therefore susceptible to
pathological insult. Thus, the GluD1-Cbln1-Neurexin complex is a highly vulnerable node for emergence of
neurocognitive disorders. GluD1 is enriched in the striatum which receives strong excitatory inputs from the cortex and
thalamus. Our preliminary results demonstrate a critical role of GluD1 in excitatory neurotransmission in medium spiny
neurons in the striatum. Our goal is to address potential cell-type and synapse-selectivity in this effect upon loss of GluD1
which will support its role as a synaptic organizer. We will pursue the following specific aims; (i) Determine the
ultrastructural localization of GluD1 in the striatum and the effect of GluD1 loss on synaptic structure. We will use a
range of complementary electron microscopy, immunohistochemistry and biochemistry methods to analyze distribution of
GluD1 in the striatum and impact of GluD1 loss on striatal synapses and potential reorganization of synaptic components.
(ii) Determine the role of GluD1 in synaptic neurotransmission and plasticity. We will use conventional electrophysiology
together with ex vivo optogenetics to stimulate specific synapses to address potential synapse-specific roles of GluD1. (iii)
Determine the role of striatal GluD1 in cognitive and behavioral control. We will address the impact of changes in
synaptic function upon loss of striatal GluD1 on emotional, cognitive and motor behaviors that are regulated by striatal
circuits. These studies will be complemented with DREADD technique to manipulate specific striatal pathways. Together,
the proposed studies will systematically address the synaptic organizational principle of GluD1 in the striatum and address
its role in synaptic and behavioral phenotypes relevant to neuropsychiatric and neurological disorders.

## Key facts

- **NIH application ID:** 11046179
- **Project number:** 7R01MH116003-06
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Shashank Manohar Dravid
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $162,849
- **Award type:** 7
- **Project period:** 2024-03-01 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11046179

## Citation

> US National Institutes of Health, RePORTER application 11046179, Function of glutamate delta-1 receptor (7R01MH116003-06). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/11046179. Licensed CC0.

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