Margarita Behrens

Senior Staff Scientist

Computational Neurobiology Laboratory

Salk Institute for Biological Studies - Margarita Behrens

Margarita Behrens


Senior Staff Scientist
Computational Neurobiology Laboratory

The goal of our research is to understand whether mental disorders, such as schizophrenia or autism, arise from subtle changes to brain circuit formation during postnatal development.

The fine balance between excitation and inhibition in brain circuits is critical for cognitive processes, and alterations in this balance can lead to mental disorders such as schizophrenia or autism. Although, symptoms of the diseases appear at different ages, it is believed they are the result of alterations in neurodevelopment, due to the interplay between genetic predisposition and environmental influences affecting the epigenome.

Our laboratory studies the role of cortical circuit development and its disruption during pre or postnatal brain development in mouse. We originally described the role of oxidative stress, specifically production of superoxide radical and the proinflammatory cytokine IL-6, as responsible for the long-term consequences of alteration of glutamatergic neurotransmission during early life. The lasting effects of perinatal or adolescent interventions have been postulated to occur through epigenetic mechanisms. DNA methylation has been postulated as the best candidate for such long-term effects of perinatal or adolescent interventions. In search of the normal patterns of DNA methylation in brain, we have produced the first whole genome maps comparing mouse and human prefrontal cortex during the lifespan. We demonstrated that DNA methylation patterns are highly dynamic, and cell-type specific through brain development in both species, and importantly, that neurons acquire a specific type on non-CG methylation coinciding with the period of synaptogenesis in both species. We recently demonstrated that non-CG methylation patterns identify specific neuronal populations at the single-cell level.

Our projects encompass basic genomics, neurochemistry/neurobiology and physiology of fast-spiking interneurons. We use electroencephalography in awake animals for analyses of network activity. The main goal of our studies is to decipher how subtle alterations in the postnatal maturation of cortical circuits can lead to persistent aberrant oscillatory activity and disruptions of cognition in adults, as observed in mental disorders.


Education

MS: Biochemistry, University of Chile, Santiago, Chile
PhD: Biochemistry and Molecular Biology, University Autonoma, Madrid, Spain
Postdoctoral training: Neurology Department Washington University School of Medicine, St Louis, Missouri.

Awards & Honors

  • FEBS predoctoral Fellowship
  • Cold Spring Harbor Laboratory Fellowship
  • EMBO fellowship
  • NARSAD Young Investigator Award
  • Daniel X. Freedman Award

Selected Publications

  • Luo C, Keown CL, Kurihara L, Zhou J, He Y, Li J, Castanon R, Lucero J, Nery JR, Sandoval JP, Bui B, Sejnowski TJ, Harkins TT, Mukamel EA*, Behrens MM*, Ecker JR*. 2017. Single-cell methylomes identify neuronal subtypes and regulatory elements in mammalian cortex. Science. 357(6351):600-604. * co-senior authors.
  • Khan A, de Jong LA, Kamenski ME, Higa KK, Lucero JD, Young JW, Behrens MM*, Powell SB*. 2016. Adolescent GBR12909 exposure induces oxidative stress, disrupts parvalbumin-positive interneurons, and leads to hyperactivity and impulsivity in adult mice. Neuroscience. 345:166-175. * co-senior authors.
  • Wang X, Pinto-Duarte A, Behrens MM, Zhou X, Sejnowski TJ. 2015. Characterization of spatio-temporal epidural event-related potentials for mouse models of psychiatric disorders. Sci Rep. 2015 Oct 13;5:14964.
  • Barnes SA, Pinto Duarte A, Kappe A Metzler A, Mukamel EA, Lucero J, Wang X, Sejnowski TJ, Markou A*, Behrens MM*. 2015. mGluR5 ablation from parvalbumin interneurons induces neurophysiological and behavioral disruptions observed in neurodevelopmental disorders. Molecular Psychiatry 20(10):1161-72. * co-senior authors.
  • Jadi M, Behrens MM, Sejnowski TJ. 2015. Abnormal gamma oscillations in NMDAR hypofunction models of schizophrenia. Biological Psychiatry 79(9):716-26.
  • Powell SB, Khan A, Young JW, Scott CN, Buell MR, Caldwell S, Tsan E, de Jong LA, Acheson DT, Lucero J, Geyer MA, Behrens MM. 2015. Early Adolescent Emergence of Reversal Learning Impairments in Isolation-Reared Rats. Dev Neurosci. 37:253-62.
  • Lister R*, Mukamel EA, Nery JR, Urich M, Puddifoot CA, Johnson ND, Lucero J, Huang Y, Dwork AJ, Schultz MD, Yu M, Tonti-Filippini J, Heyn H, Hu S, Wu JC, Rao A, Esteller M, He C, Haghighi FG, Sejnowski TJ, Behrens MM*, Ecker JR*. 2013. Global epigenomic reconfiguration during mammalian brain development. Science. 341(6146):1237905. Co-senior authors.
  • Ji B, Wang X, Pinto-Duarte A, Kim M, Caldwell S, Young JW, Behrens MM, Sejnowski TJ, Geyer MA, Zhou X. 2013. Prolonged Ketamine Effects in Sp4 Hypomorphic Mice: Mimicking Phenotypes of Schizophrenia. PLoS One. 8(6):e66327.
  • Amitai N, Kuczenski R, Behrens MM, Markou A. 2012. Repeated phencyclidine administration alters glutamate release and decreases GABA markers in the prefrontal cortex of rats. Neuropharmacology. 62(3):1422-31.
  • Powell SB, Sejnowski TJ, Behrens MM. 2012. Behavioral and neurochemical consequences of cortical oxidative stress on parvalbumin-interneuron maturation in rodent models of schizophrenia. Neuropharmacology. 62(3):1322-31.
  • Volman V, Behrens MM, Sejnowski TJ. 2011. Downregulation of Parvalbumin at Cortical GABA Synapses Reduces Network Gamma Oscillatory Activity. J. Neuroscience 31:18148-18137.
  • Behrens MM, Sejnowski TJ. 2009. Does schizophrenia arise from oxidative dysregulation of parvalbumin-interneurons in the developing cortex? Neuropharmacology 57:193-200.
  • Lodge DJ, Behrens MM, Grace AA. 2009. A loss of parvalbumin containing interneurons is associated with diminished oscillatory activity in an animal developmental model of schizophrenia. J Neuroscience 29(8):2344-54.
  • Behrens MM, Ali SS, Dugan LL. 2008. Interleukin-6 mediates the increase in NADPH-oxidase in the ketamine model of schizophrenia. J. Neuroscience 28(51):13957-66. PMC2752712.
  • Zhang Y, Behrens MM, Lisman J. 2008. Prolonged Exposure to NMDAR Antagonist Suppresses Inhibitory Synaptic Transmission in Prefrontal Cortex. Journal of Neurophysiology 100:959-965. PMC2525704.
  • Behrens MM*, Ali SS, Dao DN, Lucero J, Shekhtman G, Quick KL, Dugan LL*. 2007. Ketamine-induced Loss of Phenotype of Fast-Spiking Interneurons is Mediated by NADPH-oxidase. Science 318:1645-1647. *co-corresponding authors.
  • Kinney JW, Davis CN, Tabarean I, Conti B, Bartfai T, Behrens MM. 2006. A specific role for NR2A-containing NMDA receptors in the maintenance of parvalbumin and GAD67 immunoreactivity in cultured interneurons. J. Neuroscience 26:1604-1615