Dlx1 and Dlx2 Promote Interneuron GABA Synthesis, Synaptogenesis, and Dendritogenesis

Cereb Cortex. 2018 Nov 1;28(11):3797-3815. doi: 10.1093/cercor/bhx241.

Abstract

The postnatal functions of the Dlx1&2 transcription factors in cortical interneurons (CINs) are unknown. Here, using conditional Dlx1, Dlx2, and Dlx1&2 knockouts (CKOs), we defined their roles in specific CINs. The CKOs had dendritic, synaptic, and survival defects, affecting even PV+ CINs. We provide evidence that DLX2 directly drives Gad1, Gad2, and Vgat expression, and show that mutants had reduced mIPSC amplitude. In addition, the mutants formed fewer GABAergic synapses on excitatory neurons and had reduced mIPSC frequency. Furthermore, Dlx1/2 CKO had hypoplastic dendrites, fewer excitatory synapses, and reduced excitatory input. We provide evidence that some of these phenotypes were due to reduced expression of GRIN2B (a subunit of the NMDA receptor), a high confidence Autism gene. Thus, Dlx1&2 coordinate key components of CIN postnatal development by promoting their excitability, inhibitory output, and survival.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cerebral Cortex / cytology
  • Cerebral Cortex / growth & development*
  • Female
  • GABAergic Neurons / cytology
  • GABAergic Neurons / physiology*
  • Gene Expression Regulation, Developmental
  • Glutamate Decarboxylase / metabolism
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / physiology*
  • Interneurons / cytology
  • Interneurons / physiology*
  • Male
  • Mice, Knockout
  • Miniature Postsynaptic Potentials
  • Synapses / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / physiology*
  • Vesicular Inhibitory Amino Acid Transport Proteins / metabolism
  • gamma-Aminobutyric Acid / biosynthesis*

Substances

  • Distal-less homeobox proteins
  • Homeodomain Proteins
  • Transcription Factors
  • Vesicular Inhibitory Amino Acid Transport Proteins
  • Viaat protein, mouse
  • gamma-Aminobutyric Acid
  • Glutamate Decarboxylase
  • glutamate decarboxylase 1
  • glutamate decarboxylase 2