Dravid Lab (College Station)

Dravid Lab Research

(1) Function of schizophrenia and autism-associated glutamate delta 1 receptor in neural circuits: Genetic studies have demonstrated strong association of GRID1 gene that codes for GluD1 with autism and schizoaffective disorders but the underlying mechanisms remain poorly understood. We conducted the first detailed molecular and behavioral characterization of the GluD1 knockout model (Yadav et al., 2012; 2013; Gupta et al., 2015; Suryavanshi et al., 2016; Liu et al., 2018). We found that GluD1 KO replicates behaviors relevant to autism including social deficits, repetitive behaviors and impaired reversal learning. Furthermore, GluD1 KO mice have impaired macroautophagy and defective developmental pruning of dendritic spines which is relevant to autism pathology (Gupta et al., 2015; Suryavanshi et al., 2016; Gawande et al., 2022). Studies from Yuzaki and Tricoire laboratories have revealed strong GluD1 expression in the striatum and striatal circuits have been implicated in cognitive flexibility and repetitive behavior. Using electrophysiology and optogenetics we found that GluD1 preferentially expresses at and regulates thalamostriatal synapses originating from parafascicular nucleus and thereby regulates cognitive flexibility and repetitive behavior phenotypes (Liu et al., 2020).

(2) Therapeutic targeting of trans-synaptic mechanisms underlying chronic pain and Parkinsonism. More recently we have identified a unique role of GluD1 in the maintenance of glutamatergic synapses at the projections from lateral parabrachial nucleus to central amygdala. Dysfunction of this pathway has been well documented in chronic pain and our studies demonstrated that GluD1 contributes to this dysfunction (Gandhi et al., 2021). Specifically, we found that GluD1 and its synaptogenic partner Cbln1 are downregulated in the central amygdala in chronic pain models which leads to changes in synaptic function. Importantly, we found that this pathway can be restored by injection of recombinant Cbln1 into the central amygdala. We have collaborated with Dr. Volker Neugebauer on these studies. We have a patent-pending for a novel protein therapeutic approach to mitigate chronic pain. We are working on the translational aspect of these and other drug discovery findings. We have also recently collaborated with Dr. Hong-Yuan Chu and Dr. Yoland Smith to examine the role of striatal GluD1 and other trans-synaptic proteins in Parkinsonism.

(3) Explore NMDAR subtype roles in interneurons and astrocytes and relevance to schizophrenia, epilepsy, Parkinsonism and addiction. We have recently explored the function of NMDA receptor GluN2C and GluN2D subunits which exhibit unique distribution pattern and biophysical and pharmacological properties. We found that GluN2C was expressed in astrocytes in majority of corticolimbic region and parvalbumin neurons in other regions (Ravikrishnan et al., 2018; Alsaad et al., 2019). We found that GluN2C function in inhibitory neuron subtype in the globus pallidus was involved in Parkinsonism motor deficits (Liu et al., 2021). In astrocytes GluN2C subunit was found to contribute to maintenance of cocaine preference memory (Shelkar et al., 2022). We have developed conditional knockout models to specifically probe the NMDA hypofunction hypothesis of schizophrenia. We found that GluN2D ablation from PV interneurons contributed to perfrontal cortex hyperexcitability, impaired inhibitory circuit and emergence of schizophrenia phenotype (Gawande et al., 2023).

Techniques Utilized

Brain slice electrophysiology
Stereotaxic surgery
Immunohistochemistry and confocal imaging
Behavioral analysis
Genetic mouse model
Disease model for Parkinson’s disease and chronic pain
Drug discovery
ECoG

Lab Personnel

GAJANAN P. SHELKAR, Ph.D. – Associate Research Scientist

Research Interests:
My research focuses on unraveling the physiological significance of GluN2C- and GluN2D-containing NMDA receptors and glutamate delta-1 receptors in various neurological disorders, including addiction, epilepsy, neuropathic pain, and Parkinson's disease. I am particularly interested in exploring the novel roles of astrocytic NMDA receptors and their impact on synaptic, neuronal, and network excitability in both healthy and disease states.

Research skills and expertise:
Stereotaxic surgeries, electrophysiology, ECoG, neuropharmacology-related behavioral assays, immunohistochemistry, confocal imaging, western blotting, and transgenic animal breeding.
Google Scholar: Google Scholar Profile
PubMed: PubMed Profile

KISHORE KUMAR S. NARASIMHAN, Ph.D. – Postdoctoral Research Fellow

Research Interests:
Exploring the molecular intricacies underlying synaptic neurotransmission via ionotropic glutamate receptors (iGluRs), and their role in neuropathic pain, schizophrenia, autism, and Parkinson's disease pathogenesis. Investigating drug discovery avenues targeting iGluRs. Additionally, delving into oxidative/mitochondrial metabolism and Nrf2/ARE signaling within the heart/brain axis.

Expertise:
Proficient in neuroscience research encompassing CNS disease models, receptor pharmacology, synaptic mechanisms, and behavioral analysis; NGS techniques such as Bulk RNAseq, CLC genomics, and Galaxy for differential expression analysis; Molecular Biology and Cloning techniques such as RNA/miRNA isolation, primer design, qPCR, and site-directed mutagenesis; Biochemistry methods including Enzyme kinetics, Protein expression/purification, Immunoblotting, Immunofluorescence, Immunocytochemistry, and ELISA; Managing transgenic mouse lines, including breeding strategies, and genotyping; Cell culture techniques involving primary and secondary cell lines, differentiation, proliferation, toxicity assessment, dose determination and Protein-Protein Interactions analysis through cell binding assays.
Google Scholar: Google Scholar Profile
PubMed: PubMed Profile
ORCiD: ORCiD Profile

Sukanya Gakare, Ph.D. – Postdoctoral Research Associate

Research Interests:
Dr. Sukanya’s research work is mainly focused on understanding the role of GluN2D-containing NMDA receptors and GluD1 receptors in regulating synapses and circuits in addiction, myelination, and pain models.

Research skills and expertise:
Rodent stereotaxic surgeries, genetic mouse models and behavioral assays, immunohistochemistry and imaging, animal colony maintenance.
PubMed: PubMed Profile

Poojashree Chettiar – Medical Sciences Graduate Student

Research Interests:
I am deeply engaged in studying the synaptic and molecular mechanisms associated with neuropsychiatric disorders. My research centers on the GluD1 receptor's role in the dorsal striatum, emphasizing its influence on NMDA and AMPA receptor trafficking and PKC-dependent synaptic plasticity. Through detailed investigations into these mechanisms, I aim to better understand how disruptions in synaptic function contribute to behavioral inflexibility and repetitive behaviors, with the ultimate goal of developing targeted treatments for cognitive impairments and broader neuropsychiatric conditions such as autism, schizophrenia, and bipolar disorder.

Expertise:
Brain slice electrophysiology, basic cell culture techniques, light microscopy and imaging, neurobehavioral tests for assessing cognitive and motor function, western blotting, and ELISA.

Siddhesh Sabnis – Medical Sciences Graduate Student

Research Interests:
My research is mainly focused on understanding the role of GluD1-Cbln1 signaling in inflammatory and neuropathic pain models. Apart from this, I am also trying to understand the role of astrocytic NMDA receptors in controlling behavior.

Expertise:
Animal behavior, stereotaxic surgeries, viral injections.