Lalit Srivastava PhD
- Theme-Based Group:Environmental Adversity, Neurodevelopment, and Mental Health
- Division:Basic Neuroscience
6875 Boulevard LaSalle
Researcher, Douglas Research Centre
Full Professor, Department of Psychiatry, McGill University
Etiopathology of schizophrenia and autism
Research in our laboratory focuses on understanding the neurobiology of schizophrenia and autism using a number of approaches, including post-mortem human studies and heuristic animal models. These neurodevelopmental disorders are believed to result from an interaction between susceptibility gene(s) and early environmental risk factors leading to development of faulty neural circuits. 1. Testing the hypothesis that developmental aberrations in the hippocampus causes schizophrenia-related pathology, our work has provided evidence that neonatal lesion of the hippocampus in rat pups leads to delayed emergence of behaviors and neurochemical changes similar to those described in schizophrenia. Our recent studies show that the activity of developing ventral hippocampus neurons has a major role in the maturation of prefrontal networks and function. Using opto- and pharmacogenetic tools combined with electrophysiology, imaging and behavior, current efforts are focused on understanding the mechanistic underpinnings of ventral hippocampus regulation of prefrontal cortical development. 2. Using a schizophrenia risk gene based model, i.e., mice with mutation in dysbindin gene, we have reported that dysbindin-deficiency is associated with significant cognitive impairments and pre and post-synaptic alterations at hippocampal glutamate synapse. These studies establish novel functions of dysbindin gene in the brain which will hopefully lead to a better understanding of how variations in this gene elevate risk to schizophrenia. 3. Pre- and perinatal infections elevate the risk of developing autism and schizophrenia. Our studies in a rat maternal infection model suggest a detrimental effect of early infection on brain development and behavior. Relevant to autism and pre-morbid symptoms of schizophrenia, our studies in rats with prenatal exposure to lipopolysaccharide (LPS) show that maternal infection can lead to behavioral changes soon after birth. We showed that prenatal LPS causes altered cytoarchitecture of pyramidal neurons of the hippocampus and the prefrontal cortex and the expression of dopamine D2 receptors. Current studies aim to decipher how maternal infection interacts with genetic susceptibility (gene x environment interaction) to produce autism and schizophrenia-related pathology.
1. Bhardwaj, S.K., Zeng, Z., Zheng, W., Wong, T.P. and Srivastava, L.K. (2015), Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice. Front. Behav. Neurosci., 9:72. doi:10.3389/fnbeh. 2015.00072 .
2. Baldwin, C.H. and Srivastava, L.K. (2015) Can neurodevelopmental theory account for sex differences in schizophrenia? J. Psychiatr. Neurosci., 40(2): 75-77
3. Bhardwaj, S.K. Stojkovic, K., Kiessling, S., Srivastava, L.K., and Cermakian, N. (2015) Constant light uncovers behavioral effects of a mutation in the schizophrenia risk gene Dtnbp1 in mice. Behav Brain Res. 284, 58-68.
4. Bhardwaj SK, Tse Y, Ryan R, Wong TP, Srivastava LK (2014), Impaired adrenergic-mediated plasticity of prefrontal cortical glutamate synapses in rats with developmental disruption of the ventral hippocampus. Neuropsychopharmacology, 39, 2963-2973. PMID: 24917197
5. Ryan, R., Bhardwaj, S.K., Srivastava, L.K., and Wong, T.P. (2013), Imbalance of excitation and inhibition in the prefrontal cortex after neonatal ventral hippocampal lesion in the rat. Cerebral Cortex 23, 1198-1207. PMID: 22581849
6. Baharnoori, M., Bhardwaj, S.K., and Srivastava, L.K. (2013) Effect of maternal lipopolysaccharide administration on the development of dopaminergic receptor and transporter in the rat offspring. PLoS ONE, 8, e54439. PMID: 23349891
7. Zheng, W., Zeng, Z., Bhardwaj, S.K., Jamali, S., and Srivastava, L.K. (2013) Lithium normalizes amphetamine-induced changes in striatal FoxO1 phosphorylation and behaviors in rats. Neuroreport 24, 560-565). PMID: 23652158
8. Song, W. Zukor, H., Lin, S.H., Hascalovici, J., Lieberman, A., Tavitian, T., Mui, J, Vali, H., Tong, X.K., Bhardwaj, S.K., Srivastava, L.K. Hamel, E. and Schipper, H.M. (2012), Schizophrenia-like features in transgenic mice overexpressing human HO-1 in the astrocytic compartment. J. Neurosci. 32:10841-10853. PMID: 22875919
9. Zheng, W., Wang, H., Zeng, Z., Little, P.J., Srivastava, L.K. and Quirion, R. (2012). The possible role of the Akt signaling pathway in schizophrenia. Brain Res. 1470: 145-158. PMID: 22771711
10. Bhardwaj, S., Forcelli, P.A, Palchik, G., Gale, K., Srivastava, L.K., Kondratyev, A. (2012) Neonatal exposure to phenobarbital potentiates schizophrenia-like behavioral outcomes in the rat. Neuropharmacology 62 (2012), 2337-2345. PMID: 22366076
11. Baharnoori, M., Bhardwaj, S.K., and Srivastava, L.K. (2012) Neonatal behavioral changes in rats with gestational exposure to lipopolysaccharide: A prenatal infection model for developmental neuropsychiatric disorders. Schizophrenia Bull., 38 (2012):444-456. PMID: 20805287
A PhD in Life Sciences from J. Nehru University, New Delhi, I did post-doctoral training in the Departments of Psychiatry and Neurosciences, McMaster University, Hamilton, Canada. I joined McGill University in 1992 and am currently a full Professor in the Department of Psychiatry as well as senior scientist at the Douglas Mental Health University Institute, Montreal. My research program, funded by grants from the CIHR, NSERC, FRSQ, and NIH, aims to understand the neurobiology of schizophrenia and autism. We are particularly interested in probing the neurodevelopmental hypothesis of these disorders using rodent model systems and behavioral, molecular and electrophysiological approaches.
Chercheur National et Chercheur-Boursier Senior, Fonds de la Recherche en Santé du Québec (FRSQ).
Dr. Sanjeev Bhardwaj, Research Associate
Ms. Hannaford Edwards, Graduate student
Ms. Antonetta Joseph, Graduate student
Mr. Amit Goel, Graduate student
Altered circadian rhythms in a mouse model of neurodevelopmental disorders based on prenatal maternal immune activation. Brain Behav Immun. 2021;93:119-131.
Mice with dopaminergic neuron-specific deletion of DTNBP-1 gene show blunted nucleus accumbens dopamine release and associated behaviors. Neuropharmacology. 2021;184:108440.
Neurodevelopmental insights into circuit dysconnectivity in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2021;104:110047.
Are Circadian Disturbances a Core Pathophysiological Component of Schizophrenia? J Biol Rhythms. 2020;35(4):325-339.
The 42nd Annual Meeting of the Canadian College of Neuropsychopharmacology. J Psychiatry Neurosci. 2019;44(6):E21-E30.
Microglia in the developing prefrontal cortex of rats show dynamic changes following neonatal disconnection of the ventral hippocampus. Neuropharmacology. 2019;146:264-275.
A sexually dichotomous, autistic-like phenotype is induced by Group B Streptococcus maternofetal immune activation. Autism Res. 2017;10(2):233-245.
Loss of dysbindin-1, a risk gene for schizophrenia, leads to impaired group 1 metabotropic glutamate receptor function in mice. Front Behav Neurosci. 2015;9:72.
Can the neurodevelopmental theory account for sex differences in schizophrenia across the life span? J Psychiatry Neurosci. 2015;40(2):75-7.
Constant light uncovers behavioral effects of a mutation in the schizophrenia risk gene Dtnbp1 in mice. Behav Brain Res. 2015;284:58-68.
Impaired adrenergic-mediated plasticity of prefrontal cortical glutamate synapses in rats with developmental disruption of the ventral hippocampus. Neuropsychopharmacology. 2014;39(13):2963-73.