Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition
| Autor: | Carter W. Daniels, Trent Anderson, David M. Treiman, Michael Olive, Jason M. Newbern, Katherina P. Rees, Kenji J. Nishimura, Sara J Knowles, Shiv Shah, George R. Bjorklund, Guohui Li, Federico Sanabria, Lauren T. Hewitt, Noah R. Fry, Steven Marsh, Tanya A. Gupta, Michael C. Holter, William D. Snider |
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| Rok vydání: | 2020 |
| Předmět: |
MAPK/ERK pathway
Ganglionic eminence Cognitive Neuroscience MAP Kinase Kinase 1 Embryonic Development Inhibitory postsynaptic potential 03 medical and health sciences Cellular and Molecular Neuroscience Mice 0302 clinical medicine Organ Culture Techniques medicine Animals GABAergic Neurons 030304 developmental biology Cerebral Cortex 0303 health sciences biology Perineuronal net Electroencephalography Inhibition Psychological medicine.anatomical_structure Parvalbumins Cerebral cortex biology.protein Excitatory postsynaptic potential GABAergic Original Article Neuroscience 030217 neurology & neurosurgery Parvalbumin Locomotion Signal Transduction |
| Zdroj: | Cereb Cortex |
| ISSN: | 1460-2199 |
| Popis: | Many developmental syndromes have been linked to genetic mutations that cause abnormal ERK/MAPK activity; however, the neuropathological effects of hyperactive signaling are not fully understood. Here, we examined whether hyperactivation of MEK1 modifies the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling in a subpopulation of immature neurons in the embryonic subpallial mantle zone. Adult mutants displayed a significant loss of parvalbumin (PV), but not somatostatin, expressing CINs and a reduction in perisomatic inhibitory synapses on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype but showed signs of decreased intrinsic excitability that coincided with an increased risk of seizure-like phenotypes. In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of perineuronal nets, an extracellular structure thought to restrict plasticity. Indeed, we found that mutants exhibited a significant impairment in the acquisition of behavioral response inhibition capacity. Overall, our data suggest PV-CIN development is particularly sensitive to hyperactive MEK1 signaling, which may underlie certain neurological deficits frequently observed in ERK/MAPK-linked syndromes. |
| Databáze: | OpenAIRE |
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