mGluR5 Exerts Cell-Autonomous Influences on the Functional and Anatomical Development of Layer IV Cortical Neurons in the Mouse Primary Somatosensory Cortex

摘要

Glutamate neurotransmission refines synaptic connections to establish the precise neural circuits underlying sensory processing. Deleting metabotropic glutamate receptor 5 (mGluR5) in mice perturbs cortical somatosensory map formation in the primary somatosensory (S1) cortex at both functional and anatomical levels. To examine the cell-autonomous influences of mGluR5 signaling in the morphological and functional development of layer IV spiny stellate glutamatergic neurons receiving sensory input, mGluR5 genetic mosaic mice were generated through in utero electroporation. In the S1 cortex of these mosaic brains, we found that most wild-type neurons were located in barrel rings encircling thalamocortical axon (TCA) clusters while mGluR5 knock-out (KO) neurons were placed in the septal area, the cell-sparse region separating barrels. These KO neurons often displayed a symmetrical dendritic morphology with increased dendritic complexity, in contrast to the polarized pattern of wild-type neurons. The dendritic spine density of mGluR5 KO spiny stellate neurons was significantly higher than in wild-type neurons. Whole-cell electrophysiological recordings detected a significant increase in the frequencies of spontaneous and miniature excitatory postsynaptic events in mGluR5 KO neurons compared with neighboring wild-type neurons. Our mosaic analysis provides strong evidence supporting the cell-autonomous influence of mGluR5 signaling on the functional and anatomical development of cortical glutamatergic neurons. Specifically, mGluR5 is required in cortical glutamatergic neurons for the following processes: (1) the placement of cortical glutamatergic neurons close to TCA clusters; (2) the regulation of dendritic complexity and outgrowth toward TCA clusters; (3) spinogenesis; and (4) tuning of excitatory inputs.>SIGNIFICANCE STATEMENT Glutamatergic transmission plays a critical role in cortical circuit formation. Its dysfunction has been proposed as a core factor in the etiology of many neurological diseases. Here we conducted mosaic analysis to reveal the cell-autonomous role of the metabotropic glutamate receptor 5 (mGluR5). We found that mGluR5 is required for several key steps in wiring up the thalamocortical connections to form the cortical somatosensory map. mGluR5-dependent processes during early postnatal brain development affect the following: (1) placement of activity-directed cortical neurons; (2) regulation of polarized dendritic outgrowth toward thalamocortical axons relaying sensory information, (3) synaptogenesis; and (4) development of functional connectivity in spiny stellate neurons. Perturbing mGluR5 expression could lead to abnormal neuronal circuits, which may contribute to neurological and psychiatric disease.