Mice lacking Dlx1 show subtype-specific loss of interneurons, reduced inhibition and epilepsy.
Dlx homeodomain transcription factors are essential during embryonic development for the production of forebrain GABAergic interneurons. Here we show that Dlx1 is also required for regulating the functional longevity of cortical and hippocampal interneurons in the adult brain. We demonstrate preferential Dlx1 expression in a subset of cortical and hippocampal interneurons which, in postnatal Dlx1 mutants, show a time-dependent reduction in number. This reduction preferentially affects calretinin(+) (bipolar cells) and somatostatin(+) subtypes (for example, bitufted cells), whereas parvalbumin(+) subpopulations (basket cells and chandelier cells) seem to be unaffected. Cell transplantation analysis demonstrates that interneuron loss reflects cell-autonomous functions of Dlx1. The decrease in the number of interneurons was associated with a reduction of GABA-mediated inhibitory postsynaptic current in neocortex and hippocampus in vitro and cortical dysrhythmia in vivo. Dlx1 mutant mice show generalized electrographic seizures and histological evidence of seizure-induced reorganization, linking the Dlx1 mutation to delayed-onset epilepsy associated with interneuron loss.
Cobos
Inma
I
Nina Ireland Laboratory of Developmental Neurobiology, Department of Psychiatry, University of California San Francisco, San Francisco, California 94158, USA. icobos@itsa.ucsf.edu
Calcagnotto
Maria Elisa
ME
Vilaythong
Alex J
AJ
Thwin
Myo T
MT
Noebels
Jeffrey L
JL
Baraban
Scott C
SC
Rubenstein
John L R
JL
D000375:Aging / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001522:Behavior, Animal; D001921:Brain / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D002452:Cell Count; D002540:Cerebral Cortex / Q000503:physiopathology; D004827:Epilepsy / Q000235:genetics / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D017353:Gene Deletion; D018398:Homeodomain Proteins / Q000235:genetics*; D007395:Interneurons / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009433:Neural Inhibition; D009474:Neurons; D013569:Synapses; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
C088334:Distal-less homeobox proteins; D018398:Homeodomain Proteins; D014157:Transcription Factors; D005680:gamma-Aminobutyric Acid