It is estimated that ~1 in every 110 children is affected by autism spectrum disorders (ASDs) with devastating consequence to the individual and family along with being an economic burden. There is currently no effective therapy available for ASD and understanding the underlying mechanisms may lead to identification of novel therapeutic targets. Human genome-wide association studies have identified genetic variations that may contribute to ASDs. These studies have established that ASD-associated genes are part of a large functional network involved in synapse formation and signaling. However, the precise physiological role of several of the newly identified candidate genes is still unknown. GRID1 (Glutamate Receptor Ionotropic Delta-1) gene, which codes for the glutamate delta-1 (GluD1) subunit, is one such gene identified as a susceptibility gene for ASDs and schizoaffective disorders. Lower GluD1 expression has also been reported in ASD and schizoaffective disorder patients. Moreover, recent studies have identified a potential role of GluD1 in synapse formation via interaction with presynaptic Neurexin1, which itself is an autism susceptibility gene. These converging findings suggest that GluD1 may be a part of the functional synaptic network that is dysregulated in ASD. Our preliminary data strongly indicates that deletion of GluD1 leads to several behavioral and molecular abnormalities that resemble deficits in human ASD patients. The goal of this proposal is to specifically understand the neural basis of these abnormal behaviors in GluD1 knockout mice. Towards this end we will determine the effect of GluD1 deletion in mouse on spine morphology and synaptic function in the medial prefrontal cortex, which regulates social behaviors and cognitive abilities known to be affected in ASD patients. We have also found that an NMDA receptor agonist D-cycloserine is able to rescue social deficits in GluD1 knockout mouse. We will therefore test whether reversal of synaptic abnormalities in the medial prefrontal cortex underlie the efficacy of D-cycloserine in social deficits. These studies will provide the first evidence for a crucial role of GluD1 in the regulation of synaptic structure and function that eventually modulate behavior and potentially identify a novel therapeutic target for ASD. Additionally, our studies will support the hypothesis that facilitation of activity-dependent mechanisms may have therapeutic value in alleviating ASD phenotype.

Public Health Relevance

The incidence of autism spectrum disorder (ASD) has astonishingly increased in the past decade and there is a vast unmet need to develop novel therapies. Multiple lines of evidence suggests that GRID1 gene that codes for glutamate delta 1 (GluD1) receptor is strongly associated with a number of mental disorders including autism. However, the physiological role of GluD1 remains unknown. Proposed studies will determine the role of GluD1 in regulation of behavior and synaptic function in the prefrontal cortex and its relevance to ASD which may lead to identification of a novel therapeutic target for ASD.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Exploratory/Developmental Grants (R21)
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Developmental Brain Disorders Study Section (DBD)
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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
Gupta, Subhash C; Ravikrishnan, Aparna; Liu, Jinxu et al. (2016) The NMDA receptor GluN2C subunit controls cortical excitatory-inhibitory balance, neuronal oscillations and cognitive function. Sci Rep 6:38321
Suryavanshi, Pratyush S; Gupta, Subhash C; Yadav, Roopali et al. (2016) Glutamate Delta-1 Receptor Regulates Metabotropic Glutamate Receptor 5 Signaling in the Hippocampus. Mol Pharmacol 90:96-105
Gupta, Subhash C; Yadav, Roopali; Pavuluri, Ratnamala et al. (2015) Essential role of GluD1 in dendritic spine development and GluN2B to GluN2A NMDAR subunit switch in the cortex and hippocampus reveals ability of GluN2B inhibition in correcting hyperconnectivity. Neuropharmacology 93:274-84