Altered inhibition and excitation in neocortical circuits in congenital microcephaly
2019
Abstract Congenital
microcephalyis highly associated with intellectual disability. Features of autosomal recessive primary
microcephalysubtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the
Cyclin-dependent kinase 5regulatory subunit-associated protein 2 gene
CDK5RAP2. In the mouse,
Cdk5rap2mutations similar to the
human conditionresult in reduced
brain sizeand a strikingly thin
neocortexalready at early stages of neurogenesis that persists through adulthood. The
microcephalyphenotype in MCPH arises from a
neural stem cellproliferation defect. Here, we report a novel role for
Cdk5rap2in the regulation of dendritic development and
synaptogenesisof neocortical layer 2/3 pyramidal neurons.
Cdk5rap2-deficient murine neurons show poorly branched dendritic arbors and an increased density of immature thin spines and glutamatergic synapses in vivo . Moreover, the excitatory drive is enhanced in ex vivo brain
slice preparationsof
Cdk5rap2mutant mice. Concurrently, we show that pyramidal neurons receive fewer inhibitory inputs. Together, these findings point towards a shift in the excitation – inhibition balance towards excitation in
Cdk5rap2mutant mice. Thus, MCPH3 is associated not only with a neural progenitor proliferation defect but also with altered function of postmitotic neurons and hence with altered connectivity.
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