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.

No abstract

No abstract

No abstract

1Abnormal ERK/MAPK pathway activity is an important contributor to the neuropathogenesis of 2 many disorders including Fragile X, Rett, 16p11.2 Syndromes, and the RASopathies. Individuals with these 3 syndromes often present with intellectual disability, ADHD, autism, and epilepsy. However, the 4 pathological mechanisms that underly these deficits are not fully understood. Here, we examined whether 5 hyperactivation of MEK1 signaling modifies the development of GABAergic cortical interneurons (CINs), 6 a heterogeneous population of inhibitory neurons necessary for cortical function. We show that 7 GABAergic-neuron specific MEK1 hyperactivation in vivo leads to increased cleaved caspase-3 labeling 8 in a subpopulation of immature neurons in the embryonic subpallium. Adult mutants displayed a significant 9 loss of mature parvalbumin-expressing (PV) CINs, but not somatostatin-expressing CINs, during postnatal 10 development and a modest reduction in perisomatic inhibitory synapse formation on excitatory neurons. 11Surviving mutant PV-CINs maintained a typical fast-spiking phenotype and minor differences in intrinsic 12 electrophysiological properties. These changes coincided with an increased risk of seizure-like phenotypes. 13 In contrast to other mouse models of PV-CIN loss, we discovered a robust increase in the accumulation of 14 perineuronal nets, an extracellular structure thought to restrict plasticity in the developing brain. Indeed, we 15 found that mutants exhibit a significant impairment in the acquisition of a behavioral test that relies on 16 behavioral response inhibition, a process linked to ADHD-like phenotypes. Overall, our data suggests PV-17