RT Journal Article
SR Electronic
T1 Hyperactive MEK1 signaling in cortical GABAergic neurons causes embryonic parvalbumin-neuron death and defects in behavioral inhibition
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 748087
DO 10.1101/748087
A1 Michael C. Holter
A1 Lauren T. Hewitt
A1 Kenji J. Nishimura
A1 George R. Bjorklund
A1 Shiv Shah
A1 Noah R. Fry
A1 Katherina P. Rees
A1 Tanya A. Gupta
A1 Carter W. Daniels
A1 Guohui Li
A1 Steven Marsh
A1 David M. Treiman
A1 M. Foster Olive
A1 Trent R. Anderson
A1 Federico Sanabria
A1 William D. Snider
A1 Jason M. Newbern
YR 2019
UL http://biorxiv.org/content/early/2019/09/06/748087.abstract
AB Abnormal ERK/MAPK pathway activity is an important contributor to the neuropathogenesis of many disorders including Fragile X, Rett, 16p11.2 Syndromes, and the RASopathies. Individuals with these syndromes often present with intellectual disability, ADHD, autism, and epilepsy. However, the pathological mechanisms that underly these deficits are not fully understood. Here, we examined whether hyperactivation of MEK1 signaling 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 subpallium. Adult mutants displayed a significant loss of mature parvalbumin-expressing (PV) CINs, but not somatostatin-expressing CINs, during postnatal development and a modest reduction in perisomatic inhibitory synapse formation on excitatory neurons. Surviving mutant PV-CINs maintained a typical fast-spiking phenotype and minor differences in intrinsic electrophysiological properties. These changes 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 in the developing brain. Indeed, we found that mutants exhibit a significant impairment in the acquisition of a behavioral test that relies on behavioral response inhibition, a process linked to ADHD-like phenotypes. Overall, our data suggests PV-CIN development is particularly sensitive to hyperactive MEK1 signaling which may underlie neurological deficits frequently observed in ERK/MAPK-linked syndromes.Significance Statement The RASopathies are a family of neurodevelopmental syndromes caused by mutations that lead to increased RAS/RAF/MEK/ERK signaling and are associated with intellectual disability, epilepsy, and ADHD. We do not fully understand how distinct neuronal subtypes are affected in these syndromes. Here, we show that increased MEK signaling in developing mice promotes the embryonic death of a specific subset of cortical inhibitory neurons that express parvalbumin. Surviving mutant parvalbumin neurons also show significant changes in crucial maturation processes, which coincide with increased seizure susceptibility and profound deficits in behavioral inhibition. These data suggest that deficits in inhibitory circuit development contribute to RASopathy neuropathogenesis and indicate that therapeutic strategies targeting inhibitory interneuron dysfunction may be beneficial for these individuals.