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Dact1 cooperates with Dishevelled-1 and Disrupted in Schizophrenia-1 during postsynaptic development in mouse forebrain GABAergic interneurons

  • Author(s): Arguello, Annie
  • Advisor(s): Cheyette, Benjamin N. R.
  • Rubenstein, John L. R.
  • et al.
Abstract

Synaptogenesis has been extensively studied along with dendrite spine development in glutamatergic pyramidal neurons, however synapse development in cortical interneurons, which are largely aspiny, is comparatively less well understood. Dact1, one of 3 paralogous Dact (Dapper/Frodo) proteins in mammals, is a scaffold protein implicated in both the Wnt/β-catenin and the Wnt/Planar Cell Polarity pathways. We show here that Dact1 is expressed in migratory immature cortical interneurons. Although Dact1 is expressed in developing cortical interneurons, constitutive Dact1 mutant mice have no major defects in either the migration or numbers of these neurons. These mice do have defects in the elaboration of cortical interneuron dendrite morphology and synapse numbers along their primary dendrites. Using a conditional knock out strategy, we selectively eliminated Dact1 from cortical interneurons using a Dlx-I12b enhancer-Cre (I12bCre) allele, and thereby demonstrate a cell-autonomous role for Dact1 in postsynaptic development. Additionally, we show that synapse numbers in Dact1 deficient interneurons can be rescued by interneuron-specific expression of Dact1 itself, its binding partner Dishevelled-1, or Disrupted in Schizophrenia-1 (DISC1), a gene implicated in schizophrenia. In sum, our results support a novel cell-autonomous postsynaptic role for Dact1, in cooperation with Dishevelled-1 and DISC1, in the formation and maintenance of synapses on cortical interneuron dendrites.

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