In cortical sensory maps, thalamocortical afferents (TCAs) transmit peripheral sensations in organized arrays into distinct cortical neuronal modules to provide a topographic representation of the external sensory world. These cortical maps that form in every individual can be altered by exposure to abnormal sensory experience during a "critical period" of postnatal development. Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, schizophrenia, and congenital epilepsy. Using mouse whisker-maps as a model system, we found that metabotropic glutamate receptor 5 (mGluR5) signaling is involved in sculpting the anatomical structures and in regulating synaptic function and plasticity of thalamocortical connections. Eliminating mGluR5 function in cortical principal neurons resulted in a prolonged critical period for lesion-induced rearrangements of TCAs. Endocannabinoids (eCBs), known retrograde messengers in regulating synaptic transmission, are synthesized upon mGluR5 activation in many neurons. We hypothesize that during cortical map development mGluR5 signaling in cortical neurons instructs the anatomical modification of TCAs and that eCBs mediate, at least in part, the neural-activity dependent remodeling of thalamocortical synapses. In the proposed work we will address three specific aims: How does mGluR5 affect the development and plasticity of barrel cortex? How does mGluR5 affect functional development of cortical circuits and network activity? Do endocannabinoids mediate mGluR5 influences on developing cortical circuits? A combination of genetic, anatomical, electrophysiological, and pharmacological approaches will be employed to accomplish these aims. This study will provide a firm understanding of mGluR5 and eCBs signaling in developing neural circuits. Both mGluR5 and eCBs are potential drug targets for therapeutic interventions in humans. A detailed knowledge of their roles during neural development is critical not only for understanding normal brain function, but also to provide significant insights for the rational assessment of therapies or drug exposure (e.g., cannabis) that might affect the developing fetus.

Public Health Relevance

Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, schizophrenia, and congenital epilepsy. We are studying how neural circuits can be shaped by sensory experience with the long-term goal of developing therapies to prevent neurological disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS048884-06
Application #
8220764
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Gnadt, James W
Project Start
2004-07-01
Project End
2016-01-31
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
6
Fiscal Year
2012
Total Cost
$344,094
Indirect Cost
$125,344
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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