Loss of CC2D1A in Glutamatergic Neurons Results in Autistic-Like Features in Mice

AbstractBiallelic loss-of-function mutations in Coiled-coil and C2 domain containing 1A (CC2D1A) cause autosomal recessive intellectual disability, sometimes comorbid with other neurodevelopmental disabilities, such as autism spectrum disorder (ASD) and seizures. We recently reported that conditional deletion ofCc2d1a in glutamatergic neurons of the postnatal mouse forebrain leads to impaired hippocampal synaptic plasticity and cognitive function. However, the pathogenic origin of the autistic features of CC2D1A deficiency remains elusive. Here, we confirmed that CC2D1A is highly expressed in the cortical zones during embryonic development. Taking advantage of Cre-LoxP-mediated gene deletion strategy, we generated a novel line ofCc2d1a conditional knockout (cKO) mice by crossing floxedCc2d1a mice withEmx1-Cre mice, in which CC2D1A is ablated specifically in glutamatergic neurons throughout all embryonic and adult stages. We found that CC2D1A deletion leads to a trend toward decreased number of cortical progenitor cells at embryonic day 12.5 and alters the cortical thickness on postnatal day 10. In addition, maleCc2d1a cKO mice display autistic-like phenotypes including self-injurious repetitive grooming and aberrant social interactions. Loss of CC2D1A also results in decreased complexity of apical dendritic arbors of medial prefrontal cortex (mPFC) layer V pyramidal neurons and increased synaptic excitation/inhibition (E/I) ratio in the mPFC. Notably, chronic treatment with m...

Source: Neurotherapeutics - June 16, 2021 Category: Neurology Source Type: research