title: Deletion of Dlx1 results in reduced glutamatergic input to hippocampal interneurons.
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.
authors.affiliation: Department of Neurological Surgery, University of California, San Francisco, Box 0112, 513 Parnassus Ave., San Francisco, CA 94143, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Jones
authors.forename: MacKenzie A
authors.initials: MA
authors.lastname: Howard
authors.forename: Amelia
authors.initials: A
authors.lastname: Stanco
authors.forename: John L R
authors.initials: JL
authors.lastname: Rubenstein
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
mesh_terms: D000367:Age Factors; D000818:Animals; D056547:CA1 Region, Hippocampal / Q000502:physiology*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology*; D017353:Gene Deletion; D018698:Glutamic Acid / Q000502:physiology*; D006624:Hippocampus / Q000502:physiology; D018398:Homeodomain Proteins / Q000235:genetics; D007395:Interneurons / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D009434:Neural Pathways / Q000502:physiology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics; D005680:gamma-Aminobutyric Acid / Q000502:physiology
chemical_list: C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid