Rahul Srinivasan, PhD
Department of Neuroscience &
Interdisciplinary Program in Neuroscience (TAMU/TAMHSC)
8447 Riverside Pkwy
4012 Medical Research and Education Building
Bryan, TX 77807-3260
Education and Post-Graduate Training
MBBS, University of Mumbai, India (2000)
PhD, Department of Human Genetics, University of Pittsburgh (2006)
Postdoctoral Fellow, Division of Biology, Caltech (2007 - 2013)
Assistant Research Physiologist, Department of Physiology, UCLA (2013 - 2016)
Neurodegeneration, Parkinson’s disease, astrocytes and nicotine neuroprotection.
My research focuses on developing a mechanistic understanding of neurodegeneration, with the goal of discovering novel strategies to treat neurodegenerative disorders. In this regard, I am interested in two primary areas: (1) Understanding the role of astrocytes in neurodegeneration and (2) Elucidating molecular mechanisms underlying the known neuroprotective effects of nicotine in Parkinson’s disease.
We utilize a broad range of techniques spanning the spectrum from molecules to mice. Our methods include stereotaxic injections of adeno-associated viruses (AAVs) into the mouse brain, advanced imaging techniques such as Ca2+ imaging in live brain slices using genetically encoded calcium sensors (GCaMPs), in vitro and slice electrophysiology, advanced molecular biology, including creation of transgenic mice and tissue culture.
The role of astrocytes in neurodegeneration. Astrocytes tile the entire CNS and outnumber neurons, however, their roles in neuronal physiology and pathology are not well understood. A better understanding of the role of astrocytes in Parkinson’s disease should broadly enable the development of novel strategies to treat neurodegenerative disorders. To this end, we employ cutting edge tools and techniques to systematically study the morphology, physiology and functional consequences of substantia nigra pars compacta (SNc) astrocytes on dopaminergic neurons under normal conditions and in mouse models of Parkinson’s disease.
Mechanisms of nicotine neuroprotection in Parkinson’s disease. Tobacco use is inversely correlated with the risk of developing Parkinson’s disease (PD), but mechanisms underlying this effect remain to be elucidated. In smokers, nicotine is assumed to act via “outside-in” pharmacology, in which the drug binds to and activates neuronal nicotinic acetylcholine receptors (nAChRs) on the plasma membrane, resulting in Ca2+ influx and consequent second messenger signaling. This fails to explain neuroprotection because the steady-state plasma nicotine concentration (~100 to 200 nM) achieved in smokers cannot activate nAChRs. We suggest an alternative “inside-out” mechanism for nicotine neuroprotection that does not involve nAChR activation. We have shown that during this process, nanomolar, sub-activating concentrations of nicotine are sufficient to reduce endoplasmic reticulum (ER) stress in dopaminergic neurons via binding to and chaperoning neuronal nicotinic acetylcholine receptors (nAChRs) through the cellular secretory pathway. We are currently studying pharmacological chaperoning in mouse models of Parkinson’s disease.
(Click bibliography for a complete list of publications)
- Srinivasan R*, Lu TY*, Chai H*, Xu J, Huang BS, Golshani P, Coppola G, Khakh BS. New Transgenic Mouse Lines for Selectively Targeting Astrocytes and Studying Calcium Signals in Astrocyte Processes In Situ and In Vivo. Neuron. 2016 Dec 21;92(6):1181-1195. PMID: 27939582. *equal contribution
- Srinivasan R*, Henley BM*, Henderson BJ, Indersmitten T, Cohen BN, Kim CH, McKinney S, Deshpande P, Xiao C, Lester HA. Smoking-Relevant Nicotine Concentration Attenuates the Unfolded Protein Response in Dopaminergic Neurons. Journal of Neuroscience. 2016 Jan 6;36(1):65-79. PMID: 26740650; PMCID: PMC4701966. *equal contribution
- Srinivasan R*, Huang BS*, Venugopal S, Johnston AD, Chai H, Zeng H, Golshani P, Khakh BS. Ca2+ signaling in astrocytes from Ip3r2(-/-) mice in brain slices and during startle responses in vivo. Nature Neuroscience. 2015 May;18(5):708-17. PMID: 25894291; PMCID: PMC4429056. *equal contribution
- Srinivasan R, Henderson BJ, Lester HA, Richards CI. Pharmacological chaperoning of nAChRs: a therapeutic target for Parkinson's disease. Pharmacological Research. 2014 May;83:20-9. PMID: 24593907.
- Henderson BJ, Srinivasan R, Nichols WA, Dilworth CN, Gutierrez DF, Mackey ED, McKinney S, Drenan RM, Richards CI, Lester HA. Nicotine exploits a COPI-mediated process for chaperone-mediated up-regulation of its receptors. Journal of General Physiology. 2014 Jan;143(1):51-66. PMID: 24378908; PMCID: PMC3874574. (Featured on the cover)
- Lester HA, Miwa JM, Srinivasan R. Psychiatric drugs bind to classical targets within early exocytotic pathways: therapeutic effects. Biological Psychiatry. 2012 Dec 1;72(11):907-15. PMID: 22771239. (Featured on the cover)
- Srinivasan R, Richards CI, Xiao C, Rhee D, Pantoja R, Dougherty DA, Miwa JM, Lester HA. Pharmacological chaperoning of nicotinic acetylcholine receptors reduces the endoplasmic reticulum stress response. Molecular Pharmacology. 2012 Jun;81(6):759-69. PMID: 22379121; PMCID: PMC3362896.
- Richards CI, Srinivasan R, Xiao C, Mackey ED, Miwa JM, Lester HA. Trafficking of α4* nicotinic receptors revealed by superecliptic phluorin: effects of a beta4 amyotrophic lateral sclerosis-associated mutation and chronic exposure to nicotine. Journal of Biological Chemistry. 2011 Sep 9;286(36):31241-9. PMID: 21768117; PMCID: PMC3173132.
- Xiao C*, Srinivasan R*, Drenan RM, Mackey ED, McIntosh JM, Lester HA. Characterizing functional α6β2 nicotinic acetylcholine receptors in vitro: mutant β2 subunits improve membrane expression, and fluorescent proteins reveal responsive cells. Biochemical Pharmacology. 2011 Oct 15;82(8):852-61. PMID: 21609715; PMCID: PMC3162078. *equal contribution
- Srinivasan R, Pantoja R, Moss FJ, Mackey ED, Son CD, Miwa J, Lester HA. Nicotine up-regulates α4β2 nicotinic receptors and ER exit sites via stoichiometry-dependent chaperoning. Journal of General Physiology. 2011 Jan;137(1):59-79. PMID: 21187334; PMCID: PMC3010053. (Featured on the cover)
- Lester HA, Xiao C, Srinivasan R, Son CD, Miwa J, Pantoja R, Banghart MR, Dougherty DA, Goate AM, Wang JC. Nicotine is a selective pharmacological chaperone of acetylcholine receptor number and stoichiometry. Implications for drug discovery. AAPS Journal. 2009 Mar;11(1):167-77. PMID: 19280351; PMCID: PMC2664890.
- Srinivasan R, Wolfe D, Goss J, Watkins S, de Groat WC, Sculptoreanu A, Glorioso JC. Protein kinase C epsilon contributes to basal and sensitizing responses of TRPV1 to capsaicin in rat dorsal root ganglion neurons. European Journal of Neuroscience. 2008 Oct;28(7):1241-54. PMID: 18973552; PMCID: PMC3111963. (cover article)
- Srinivasan R, Huang S, Chaudhry S, Sculptoreanu A, Krisky D, Cascio M, Friedman PA, de Groat WC, Wolfe D, Glorioso JC. An HSV vector system for selection of ligand-gated ion channel modulators. Nature Methods. 2007 Sep;4(9):733-9. PMID: 17676048; PMCID: PMC3133941.