title: mGluR5 Exerts Cell-Autonomous Influences on the Functional and Anatomical Development of Layer IV Cortical Neurons in the Mouse Primary Somatosensory Cortex.
abstract: 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.
  
  
  
  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.
authors: The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, Program in Developmental Biology and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, and.
authors: Carlos J
authors: 0000-0002-3892-9603
authors: CJ
authors: Ballester-Rosado
authors: The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, and.
authors: Hao
authors: H
authors: Sun
authors: The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, and Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405.
authors: Jui-Yen
authors: JY
authors: Huang
authors: The Cain Foundation Laboratories, Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas 77030, Program in Developmental Biology and Department of Pediatrics, Baylor College of Medicine, Houston, Texas 77030, and Linda and Jack Gill Center, Department of Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405 hclu@indiana.edu.
authors: Hui-Chen
authors: HC
authors: Lu
mesh_terms: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism; D049229:Dendritic Spines / Q000378:metabolism; D004558:Electric Stimulation; D004622:Embryo, Mammalian; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000235:genetics; D005260:Female; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism / Q000648:ultrastructure; D018408:Patch-Clamp Techniques; D020648:Peptide Elongation Factor 1 / Q000235:genetics / Q000378:metabolism; D064529:Receptor, Metabotropic Glutamate 5 / Q000235:genetics / Q000378:metabolism*; D013003:Somatosensory Cortex / Q000166:cytology* / Q000254:growth & development*; D014633:Valine / Q000031:analogs & derivatives / Q000494:pharmacology; D050599:Vesicular Glutamate Transport Protein 2 / Q000378:metabolism; D014738:Vibrissae / Q000294:innervation
chemical_list: D018750:6-Cyano-7-nitroquinoxaline-2,3-dione; D051792:Basic Helix-Loop-Helix Proteins; D018690:Excitatory Amino Acid Agonists; D049452:Green Fluorescent Proteins; D009419:Nerve Tissue Proteins; D020648:Peptide Elongation Factor 1; D064529:Receptor, Metabotropic Glutamate 5; D014633:Valine; D050599:Vesicular Glutamate Transport Protein 2; C110701:Neurod6 protein, mouse; C493477:Slc17a6 protein, mouse; C056639:2-amino-5-phosphopentanoic acid
keywords: barrels; dendritogenesis; mGluRs; somatosensory