The goal of our research is to understand whether mental disorders, such as schizophrenia, arise from subtle changes to brain circuits during brain 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. Although the full symptoms of the disease appears in late adolescence/early adulthood, schizophrenia may be the result of alterations in neurodevelopment, due to the interplay between genetic predisposition and environmental influences.

In schizophrenia brain samples there is a decreased expression of the main enzyme responsible for GABA synthesis, specifically in the subset of fast-spiking inhibitory neurons expressing the calcium binding protein parvalbumin (PV). PV-interneurons contribute to the generation of gamma oscillations involved in working memory. Gamma oscillatory activity has a protracted maturation during postnatal brain development in mice and humans, which coincides with the maturation of PV interneurons. Thus, a disruption of the maturation of PV-interneurons may lead later to problems with executive function.

Our laboratory studies the molecular mechanisms of the pro-psychotic effects of NMDA receptor antagonists in rodents as a validated model of schizophrenia. We originally described the role of oxidative stress, specifically production of superoxide radical and the proinflammatory cytokine IL-6, as the initial event after NMDA-R antagonist exposures leading to the loss of GABAergic markers and dysfunction of the fast-spiking parvalbumin positive subset of interneurons in cortex. We next demonstrated that a similar mechanism is activated when NMDA receptors are blocked during a critical period of postnatal development, producing lasting alterations of PV+ fast-spiking interneurons as observed in schizophrenia postmortem brain samples.

One possible mechanism by which alterations during critical periods of neurodevelopment may lead to the lasting network alterations observed in adulthood is changes in the epigenome, specifically DNA methylation patterns. We have recently shown that the epigenetic landscape in the frontal cortex of human and mice is highly dynamic, and that neurons in particular show profound changes in their epigenome during early postnatal development that coincide with the period of synaptogenesis and the initiation of the maturation of PV+ interneurons.

 

We use in vitro and in vivo approaches to characterize the molecular mechanisms underlying the heightened sensitivity of parvalbumin-positive fast-spiking interneurons in animal models of schizophrenia. 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 PV-interneurons can lead to persistent aberrant oscillatory activity and disruptions of cognition in adults, as observed in schizophrenia and other mental disorders.

 

Recent Publications:

        Jadi M, Behrens MM, Sejnowski TJ. 2015. Abnormal gamma oscillations in NMDAR hypofunction models of schizophrenia. Biological Psychiatry (Epub ahead of print).

        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. Issue Cover) PMC4583365