Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionarily conserved protein, originally identified as a nuclear factor-B activator through a large-scale screen of human genes. Mutations in the human Cc2d1a gene result in autosomal recessive nonsyndromic intellectual disability. It remains unclear, however, how Cc2d1a mutation leads to alterations in brain function. Here, we have taken advantage of Cre/loxP recombinase-based strategy to conditionally delete Cc2d1a exclusively from excitatory neurons of male mouse forebrain to examine its role in hippocampal synaptic plasticity and cognitive function. We confirmed the expression of CC2D1A protein and mRNA in the mouse hippocampus. Double immunofluorescence staining showed that CC2D1A is expressed in both excitatory and inhibitory neurons of the adult hippocampus. Conditional deletion of Cc2d1a (cKO) from excitatory neurons leads to impaired performance in object location memory test and altered anxiety-like behavior. Consistently, cKO mice displayed a deficit in the maintenance of LTP in the CA1 region of hippocampal slices. Cc2d1a deletion also resulted in decreased complexity of apical and basal dendritic arbors of CA1 pyramidal neurons. An enhanced basal Rac1 activity was observed following Cc2d1a deletion, and this enhancement was mediated by reduced SUMO-specific protease 1 (SENP1) and SENP3 expression, thus increasing the amount of Rac1 SUMOylation. Furthermore, partial blockade of Rac1 activity rescued impairments in LTP and object location memory performance in cKO mice. Together, our results implicate Rac1 hyperactivity in synaptic plasticity and cognitive deficits observed in Cc2d1a cKO mice and reveal a novel role for CC2D1A in regulating hippocampal synaptic function.

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Biallelic 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 of Cc2d1a 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 of Cc2d1a conditional knockout (cKO) mice by crossing floxed Cc2d1a mice with Emx1-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, male Cc2d1a 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 minocycline rescues behavioral and morphological abnormalities, as well as E/I changes, in male Cc2d1a cKO mice. Together, these findings indicate that male Cc2d1a cKO mice recapitulate autistic-like phenotypes of human disorder and suggest that minocycline has both structural and functional benefits in treating ASD.