Molecular Mechanisms of Cortical Map Development
Precise neuronal connections are needed to ensure proper brain function. One prominent organization in the mammalian brain is the topographical representation of the external sensory world. Familiar examples are the homunculus map in the primary somatosensory (S1) cortex representing the body surface and the retinotopic map in visual cortex. Remarkably, the cortical maps that form in every individual can be modified according to sensory experience during a “critical period” of postnatal development.
In mice, sensory afferents relaying sensory information from a single whisker innervates one discrete cluster of cortical neurons that form “barrels” in the primary somatosensory cortex. We found that the metabotropic glutamate receptor 5 (mGluR5), known for its role in synaptic plasticity, is required for the development of whiser-related pattern throughout the trigeminal system. An mGluR5 loss-of-function mutation leads to enhanced “LTD-type” synaptic plasticity and prolongs the critical period of lesion-induced map plasticity.
In addition, our preliminary studies showed that eliminating mGluR5 function solely in cortical neurons, not only affects the whisker-related organization of cortical neurons (barrels) but also influences the patterning of their presynaptic partners, the thalamocortical afferents (TCAs), in normal development as well as during experience-guided remodeling. We hypothesize that mGluR5 mediated activity-dependent processes are required to coordinate the dendritic morphogenesis of layer IV neurons and the axonal arborizations of TCAs as barrels are formed.
Furthermore, we propose that mGluR5 signaling in cortical neurons restrains the anatomical modification of thalamocortical (TC) synapses triggered by abnormal sensory experience. The goal of this proposal is to elucidate activity-dependent mechanisms underlying cortical map development and plasticity with a combination of anatomical, genetic, pharmacological, and electrophysiological approaches. The specific aims include:
- to determine w hen and where mGluR5 is required during the development and plasticity of barrel cortex;
- to elucidate how does mGluR5 in cortical neurons affect synaptic function and plasticity at TC synapses.
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 signaling in developing neural circuits. mGluR5 is a potential drug target for therapeutic interventions in humans. A detailed knowledge of its roles in neural development is critical not only for understanding normal brain function but also to provide significant I nsights for the rational assessment of therapies that might affect the developing fetus.
Relevance of the project to IDDRC mission:
This research focuses on elucidating the molecular mechanism of cortical map development and plasticity. Mis-wiring of neuronal circuits during early life is likely to be a major cause of neurological disorders, including autism, dyslexia, schizophrenia, and congenital epilepsy. A better understanding the mechanisms underlying such activity-dependent processes for cortical map development will bring us closer to understanding normal brain function and also provide significant insights for the development of therapeutic strategies to treat neurological disorders.