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