Hyperactive MEK1 signaling in cortical GABAergic interneurons causes embryonic parvalbumin-neuron death and deficits in behavioral inhibition

Abnormal ERK/MAPK pathway activity is a contributor to multiple neurodevelopmental disorders, especially the RASopathies, which are associated with intellectual disability, ADHD, autism, and epilepsy. Here, we examined whether ERK/MAPK signaling regulates the development of GABAergic cortical interneurons (CINs), a heterogeneous population of inhibitory neurons necessary for cortical function. We show that ERK1/2 is not required for the initial establishment of CIN number. However, hyperactivation of MEK1 leads to increased caspase-3 activation in the embryonic subpallium and a selective loss of mature parvalbumin-expressing (PV) CINs. Surviving mutant PV-CINs have a typical fast-spiking phenotype but display a robust increase in perineuronal net accumulation. Hyperactive MEK1 mutant mice exhibit a reduction in perisomatic inhibitory synapses and seizure-like phenotypes. We also detected altered PFC development and impaired behavioral response inhibition in mutants. Our data suggests PV-CIN development is particularly sensitive to hyperactive MEK1 signaling which may underlie neurological phenotypes frequently observed in ERK/MAPK-linked syndromes