Deletion of Dlx1 Results in Reduced Glutamatergic Input to Hippocampal Interneurons

J Neurophysiol. 2011 May;105(5):1984-91. doi: 10.1152/jn.00056.2011. Epub 2011 Feb 16.

Abstract

Dlx transcription factors are important in the differentiation of GABAergic interneurons. In mice lacking Dlx1, early steps in interneuron development appear normal. Beginning at ∼ 1 mo of age, primarily dendrite-innervating interneuron subtypes begin to undergo apoptosis in Dlx1(-/-) mice; this is accompanied by a reduction in GABAergic transmission and late-onset epilepsy. The reported reduction of synaptic inhibition is greater than might be expected given that interneuron loss is relatively modest in Dlx1(-/-) mice. Here we report that voltage-clamp recordings of CA1 interneurons in hippocampal slices prepared from Dlx1(-/-) animals older than postnatal day 30 (>P30) revealed a significant reduction in excitatory postsynaptic current (EPSC) amplitude. No changes in EPSCs onto interneurons were observed in cells recorded from younger animals (P9-12). Current-clamp recordings from interneurons at these early postnatal ages showed that interneurons in Dlx1(-/-) mutants were immature and more excitable, although membrane properties normalized by P30. Terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling, caspase-3, and NeuN staining did not reveal frank cell damage or loss in area CA3 of hippocampal sections from adult Dlx1(-/-) mice. Delayed interneuron maturation may lead to interneuron hyperexcitability, followed by a compensatory reduction in the strength of excitatory transmission onto interneurons. This reduced excitation onto surviving interneurons, coupled with the loss of a significant fraction of GABAergic inputs to excitatory neurons starting at P30, may underlie cortical dysrhythmia and seizures previously observed in adult Dlx1(-/-) mice.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Age Factors
  • Animals
  • CA1 Region, Hippocampal / physiology*
  • Excitatory Postsynaptic Potentials / physiology*
  • Gene Deletion*
  • Glutamic Acid / physiology*
  • Hippocampus / physiology
  • Homeodomain Proteins / genetics
  • Interneurons / physiology*
  • Mice
  • Mice, Knockout
  • Neural Pathways / physiology
  • Transcription Factors / deficiency*
  • Transcription Factors / genetics
  • gamma-Aminobutyric Acid / physiology

Substances

  • Distal-less homeobox proteins
  • Homeodomain Proteins
  • Transcription Factors
  • Glutamic Acid
  • gamma-Aminobutyric Acid