The 16p11.2 Deletion Mouse Model of Autism Exhibits Altered Cortical Progenitor Proliferation and Brain Cytoarchitecture Linked to the ERK MAPK Pathway

Abstract

Autism spectrum disorders are complex, highly heritable neurodevelopmental disorders affecting ϳ1 in 100 children. Copy number variations of human chromosomal region 16p11.2 are genetically linked to 1% of autism-related disorders. This interval contains the MAPK3 gene, which encodes the MAP kinase, ERK1. Mutations in upstream elements regulating the ERK pathway are genetically linked to autism and other disorders of cognition including the neuro-cardio-facial cutaneous syndromes and copy number variations. We report that a murine model of human 16p11.2 deletion exhibits a reduction in brain size and perturbations in cortical cytoarchitecture. We observed enhanced progenitor proliferation and premature cell cycle exit, which are a consequence of altered levels of downstream ERK effectors cyclin D1 and p27Kip1 during mid-neurogenesis. The increased progenitor proliferation and cell cycle withdrawal resulted in premature depletion of progenitor pools, altering the number and frequency of neurons ultimately populating cortical lamina. Specifically, we found a reduced number of upper layer pyramidal neurons and an increase in layer VI corticothalamic projection neurons, reflecting the altered cortical progenitor proliferation dynamics in these mice. Importantly, we observed a paradoxical increase in ERK signaling in mid-neurogenesis in the 16p11.2del mice, which is coincident with the development of aberrant cortical cytoarchitecture. The 16p11.2del mice exhibit anxiety-like behaviors and impaired memory. Our findings provide evidence of ERK dysregulation, developmental abnormalities in neurogenesis, and behavioral impairment associated with the 16p11.2 chromosomal deletion.

16p11.2 Deletion mice display cognitive deficits in touchscreen learning and novelty recognition tasks

“…(E,F ) Automated scoring of cohort 1 confirmed the novel object recognition deficits detected by manual scoring (A) and the absence of side bias during familiarization (B). Taken together with previous findings (Portmann et al 2014;Pucilowska et al 2015), these data indicate that novel object recognition deficits in 16p11.2 heterozygotes housed in mixed-genotype cages are replicable in different cohorts, tested in different equipment, in different laboratories, and scored using different methods. ( * ) P , 05 novel object versus familiar object.…”

“…Notably, the Mills 16p11.2+/2 mice exhibited impaired contextual conditioning (Tian et al 2015). This deficit was attributed to reduced ERK1 protein levels found in the +/2 mouse brain by two groups (Pucilowska et al 2015;Tian et al 2015). While novel object recognition deficits were detected in both lines of 16p11.2+/2, contextual conditioning deficits were only detected in the Mills line.…”

“…Further, novel object recognition deficits were detected by the Landreth laboratory using the Mills line of 16p11.2 +/2 (Pucilowska et al 2015), highlighting the generalizability of impaired novel object learning and memory in two independent mutant lines with the same deletion. Using the same testing apparatus and similar procedures, we extended the novel object recognition findings by showing that object location memory, a hippocampus-dependent task (Manns and Eichenbaum 2009;Kesner and Hunsaker 2010;Poplawski et al 2014), was also impaired in +/2.…”

“…Neuroanatomical defects detected in the Dolmetsch line of 16p11.2+/2 mice included reduced cortical thickness, increased relative volume of nucleus accumbens and globus pallidus, and other anatomical abnormalities in major output regions of the basal ganglia pathway (Portmann et al 2014). Similarly, altered cortical neurogenesis was suggested, based on reduced cortical thickness and reduced numbers of Pax6+ progenitor cells and Satb2+ callosal projection neurons in both the Dolmetsch and Mills 16p11.2+/2 (Portmann et al 2014;Pucilowska et al 2015).…”

“…Novel object recognition deficits were detected in +/2 of both lines (Portmann et al 2014;Pucilowska et al 2015). Deficits in contextual conditioning and passive avoidance were reported for the Mills line (Tian et al 2015).…”