Shashank M. Dravid, B.V.Sc. & A.H., PhD, MBA

I am a neuropharmacologist trained in veterinary medicine and basic neuroscience and receptor pharmacology. My research interests are in glutamate receptor physiology and pharmacology and we have examined the roles of glutamate receptors in diseases such as schizophrenia, autism, Parkinson’s disease, epilepsy and chronic pain. Work from my lab has been primarily on the orphan glutamate delta 1 receptors and the lesser explored NMDA receptor subunits GluN2C and GluN2D.

Using genetically modified mouse models together with techniques such as brain slice electrophysiology, confocal imaging, optogenetics, chemogenetics and behavioral analysis my laboratory has discovered the circuit mechanism by which GluD1 regulates phenotypes such as behavioral flexibility and repetitive behavior. We have also identified the role of central amygdala GluD1 in chronic pain and identified novel therapeutic approaches based on GluD1-Cbln1 for the treatment of chronic pain. We have demonstrated a novel mechanism by which NMDA receptors in astrocytes are responsible for the maintenance of cocaine preference memory. Furthermore, we have discovered that GluN2D subunit of NMDA receptors in parvalbumin neurons regulates schizophrenia-related molecular network and behavioral and neural circuit phenotypes. These studies have been supported by grants from several federal institutes (National Science Foundation and National Institutes of Health) as well as foundations (Brain and Behavior Foundation, Epilepsy Foundation).

Research goals

The main goals of the research of my laboratory are:

(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:

1. Brain slice electrophysiology
2. Stereotaxic surgery
3. Immunohistochemistry and confocal imaging
4. Behavioral analysis
5. Genetic mouse model
6. Disease model for Parkinson’s disease and chronic pain
7. Drug discovery
8. ECoG

Funding

1.  NIH/National Institute of Neurological Disorders and Stroke: NIH R01

Project title: Trans-synaptic signaling complex in amygdala pain mechanisms.

Period: 08/01/2020-07/31/2025. (Scored at 11^th percentile)

Description: The goal of this project is to address the mechanisms underlying formation and plasticity of parabrachio-amygdala synapses relevant to nociception.

Role: Principal investigator       MPI:Volker Neugebauer (TTUHSC) Co-investigators: Yoland Smith (Emory), Guangchen Ji (TTUHSC)

 2. NIH/National Institute of Mental Health: NIH R01

Project title: Function of glutamate delta-1 receptor.

Period: 08/03/2018-05/31/2024 No cost extension. (Scored at 5^th percentile)

Description: The goal is to address the role of glutamate delta-1 receptor as a synaptic organizer using striatum as a model system.

Role: Principal investigator               Co-investigators: Yoland Smith (Emory)

 3.  NIH/National Institute of Neurological Disorders and Stroke: NIH R21

Project title: Structure-function and signaling of glutamate delta 1 in pain mechanism.

Period: 01/01/2023-12/31/2024.

Description: The goal of this project is to address the structure-function relationship of different domains of glutamate delta 1 to chronic pain mechanism in the central amygdala.

Role: Principal investigator