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. 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 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.

Public Health Relevance

The glutamate delta receptors are a unique class of receptors that work in a non-canonical fashion to establish synaptic connectivity. We propose to study the function of glutamate delta 1 subunit which is associated with mental disorders. The expected outcomes will provide novel understanding of GluD1 subunit as it relates to striatal synaptic function and occurrence of behavioral abnormalities. Since dysregulation of striatal circuits is a neuropathology in neurodevelopmental disorders and neurological disorders identification of pathways underlying striatal dysfunction have important therapeutic implications.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Nadler, Laurie S
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Creighton University
Schools of Medicine
United States
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Liu, Jinxu; Gandhi, Pauravi J; Pavuluri, Ratnamala et al. (2018) Glutamate delta-1 receptor regulates cocaine-induced plasticity in the nucleus accumbens. Transl Psychiatry 8:219