Hyperactive MEK1 Signaling in Cortical GABAergic Neurons Promotes Embryonic Parvalbumin Neuron Loss and Defects in Behavioral Inhibition

Michael C. Holter, Lauren T. Hewitt, Kenji J. Nishimura, Sara J. Knowles, George R. Bjorklund, Shiv Shah, Noah R. Fry, Katherina P. Rees, Tanya A. Gupta, Carter W. Daniels, Guohui Li, Steven Marsh, David Michael Treiman, Michael Foster Olive, Trent R. Anderson, Federico Sanabria, William D. Snider, Jason M. Newbern

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3064-3081
Number of pages18
JournalCerebral cortex (New York, N.Y. : 1991)
Volume31
Issue number6
DOIs
StatePublished - May 10 2021

Keywords

  • ADHD
  • ERK1/2
  • RASopathy
  • development
  • ganglionic eminence

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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