(30 lines) Experimental evidence supports the model that an imbalance in inhibitory and excitatory activity contributes to many neurological disorders including epilepsy, schizophrenia, anxiety, autism spectrum disorders and attention deficit/hyperactivity disorder. In the cerebral cortex, gamma-aminobutyric acid (GABA)ergic cortical interneurons are the major source of inhibition and are known to be critical in maintaining activity balance in the mature animal. However, the notion that developmental perturbations in GABAergic activity lead to defects in the formation of cortical circuits with lasting structural and functional deficits that provide the substrate for neurological illness, has not been explored in detail. The long-term goal of this research is to uncover how early interneuron dysfunction in the developing pre and postnatal brain leads to lasting neurological pathologies. The objective of this proposal is to reveal how extrinsic cues (nurture) and genetic programs (nature) conspire to control interneuron circuit assembly during critical windows of perinatal development. To this end, we will use the murine barrel cortex as a well-established model for the study of activity-dependent circuit maturation and one that is inherently and robustly linked to the animal's extrinsic environment. Sensory experience induces plasticity of sensory circuits in the cerebral cortex and is essential for sculpting neuronal connectivity. However, the precise role of a diversity of specific interneuron subtypes in this process is incompletely understood. We will focus our studies in cortical interneurons since our previous work indicates that these neurons are exquisitely sensitive to environmental perturbations in the neonate. In the near term, this proposal is aimed at revealing the identity interneurons subtypes that are activated by sensory cues (Aim 1). In addition, this project will assess how activity-dependent genetic programs regulate the emergence of early connectivity (Aim 2). Finally, we wish to investigate the role of cortical interneurons in the formation of sensory maps (Aim 3). With respect to outcomes, our work is expected to identify neuronal types that regulate the emergence of functional interneuron circuits. Given the accumulating experimental evidence implicating interneuron dysfunction in brain disorders, understanding the mechanisms underlying activity-dependent plasticity for these interneurons can provide invaluable insights for the development of therapeutic strategies

Public Health Relevance

Neurological illnesses such as autism spectrum disorders, schizophrenia and epilepsy are thought to arise during the development of the nervous system. Increasing experimental evidence points towards imbalances between the excitatory and inhibitory circuits in the brain as a prominent component in the etiology of these illnesses. This project is aimed at further our understanding on how electrical activity affects early brain maturation during critical periods of development with an emphasis on inhibitory neurons.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
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Panchision, David M
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Weill Medical College of Cornell University
Schools of Medicine
New York
United States
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Che, Alicia; Babij, Rachel; Iannone, Andrew F et al. (2018) Layer I Interneurons Sharpen Sensory Maps during Neonatal Development. Neuron 99:98-116.e7
Kabir, Z D; Che, A; Fischer, D K et al. (2017) Rescue of impaired sociability and anxiety-like behavior in adult cacna1c-deficient mice by pharmacologically targeting eIF2?. Mol Psychiatry 22:1096-1109
Babij, Rachel; De Marco Garcia, Natalia (2016) Neuronal activity controls the development of interneurons in the somatosensory cortex. Front Biol (Beijing) 11:459-470