Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice

Abstract

The human microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in deletion carriers. The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult mice. These data provide a strong rationale for therapeutic approaches to this disorder.

Copy Number Variation at 16p11.2 Imparts Transcriptional Alterations in Neural Development in an hiPSC-derived Model of Corticogenesis

“…SELE, CALML6, RAF1, SEMA4A). This finding supports existing work suggesting that the Erk1 MAPK pathway, which has been shown to modulate the proliferation of cortical progenitors, may drive phenotypic abnormalities associated with the 16p11.2 CNV 38,59 . Although we detected a decrease in MAPK3 gene expression in all the 16p11.2 deletion lines [ Supplementary Figure 5A], we did not observe any changes in NPC proliferation between wild type and deletion lines indicating that MAPK3 may not influence neocortical progenitor cell proliferation in these 16p11.2 patient lines [Supplementary Figure 4A].…”

“…Interestingly, transcriptional and phenotypic abnormalities have also been observed in hiPSC-derived cortical neural stem cells derived from individuals with idiopathic ASD 36,37 . The 16p11.2 deletion has widespread effects on signaling pathways that underpin critical neural progenitor functions, including proliferation and fate choice 38 , yet 16p11.2 CNV-related alterations in gene expression patterns have not been examined in early neuroepithelial precursors (radial glia), the stem and progenitor cells of the developing cortex.…”

Cortical Organoids Model Early Brain Development Disrupted by 16p11.2 Copy Number Variants in Autism

“…Transcriptome profiling of lymphoblastoid cell lines of 16p11.2 CNV human carriers identified expression dysregulation of neuronal-related gene in deletion, but not in duplication (Luo et al, 2012). Dysregulation of ciliopathy genes (Migliavacca et al, 2015), ERK/MAPK signaling (Pucilowska et al, 2018;Pucilowska et al, 2015), and metabotropic glutamate receptor 5 (mGluR5)-dependent synaptic plasticity and protein synthesis (Tian et al, 2015) in mouse models were all shown to play a role. Despite the progress made with regard to understanding of the general mechanisms disrupted by the 16p11.2 CNV, the question of how 16p11.2 variants impact early human brain development remains unanswered.…”

Hyperactive MEK1 signaling in cortical GABAergic neurons causes embryonic parvalbumin-neuron death and defects in behavioral inhibition

“…The ERK/MAPK cascade is a commonly utilized intracellular signaling pathway that is dynamically activated during embryogenesis and in adulthood. In the embryonic ventricular zone, neural progenitors typically show high levels of P-ERK1/2 relative to immature post-mitotic neurons (Pucilowska et al, 2018; Stanco et al, 2014). In adult cortices, elevated P-ERK1/2 labeling is enriched in a heterogeneous set of excitatory PNs, primarily in layer 2, and plays a critical role in long-range PN development (Cancedda et al, 2003; Gauthier et al, 2007; Holter et al, 2019; Pham et al, 2004; Pucilowska et al, 2012; Suzuki et al, 2004; Xing et al, 2016).…”