期刊
CEREBRAL CORTEX
卷 31, 期 6, 页码 3064-3081出版社
OXFORD UNIV PRESS INC
DOI: 10.1093/cercor/bhaa413
关键词
ADHD; development; ERK1/2; ganglionic eminence; RASopathy
资金
- National Institute of Health [R00NS076661, R01NS097537, R01NS087031, R01NS031768]
Many developmental syndromes are associated with genetic mutations affecting ERK/MAPK pathways, but the specific neurobiological effects of hyperactive signaling remain unclear. This study found that hyperactivation of MEK1 in GABAergic cortical interneurons led to abnormal neuronal development and functionality, resulting in deficits in inhibitory synapses, increased risk of seizures, and impaired behavioral responses. These findings shed light on the potential mechanisms underlying neurological deficits in ERK/MAPK-related syndromes.
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.
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