Altered inhibition and excitation in neocortical circuits in congenital microcephaly

• Published in: Neurobiology of disease 2019-09, Vol.129, p.130-143
• Main Authors: Zaqout, Sami, Blaesius, Kathrin, Wu, Yuan-Ju, Ott, Stefanie, Kraemer, Nadine, Becker, Lena-Luise, Rosário, Marta, Rosenmund, Christian, Strauss, Ulf, Kaindl, Angela M.
• Format: Article
• Language: English
• Subjects: Animals; Cdk5rap2; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell Differentiation - physiology; Dendritic morphogenesis; Mice; Mice, Mutant Strains; Microcephaly; Microcephaly - genetics; Microcephaly - metabolism; Microcephaly - physiopathology; Mutation; Neocortex - metabolism; Neocortex - physiopathology; Neural Pathways - metabolism; Neural Pathways - physiopathology; Neurogenesis - physiology; Neuronal differentiation; Pyramidal Cells - metabolism; Pyramidal Cells - pathology; Synaptic transmission; Synaptic Transmission - physiology
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2019.05.008

Congenital microcephaly is highly associated with intellectual disability. Features of autosomal recessive primary microcephaly subtype 3 (MCPH3) also include hyperactivity and seizures. The disease is caused by biallelic mutations in the Cyclin-dependent kinase 5 regulatory subunit-associated protein 2 gene CDK5RAP2. In the mouse, Cdk5rap2 mutations similar to the human condition result in reduced brain size and a strikingly thin neocortex already at early stages of neurogenesis that persists through adulthood. The microcephaly phenotype in MCPH arises from a neural stem cell proliferation defect. Here, we report a novel role for Cdk5rap2 in the regulation of dendritic development and synaptogenesis of 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 preparations of Cdk5rap2 mutant 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 Cdk5rap2 mutant 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. •Neuropsychiatric dysfunctions in MCPH are not explained by smaller brain alone.•an/an mice display reduced dendritic arborization in layer 2/3 neocortical pyramidal neurons.•layer 2/3 neurons of an/an mice receive increased excitation but decreased inhibition.•Excitation/inhibition imbalance is due changed proportions of excitatory/inhibitory synapses.