Deletion of Dlx 1 results in reduced glutamatergic input to hippocampal interneurons 1 2

23 Dlx transcription factors are important in the differentiation of GABAergic interneurons. In mice 24 lacking Dlx1, early steps in interneuron development appear normal. Beginning around one 25 month of age, primarily dendrite-innervating interneuron subtypes begin to undergo apoptosis in 26 Dlx1 mice; this is accompanied by a reduction in GABAergic transmission and late-onset 27 epilepsy. The reported reduction of synaptic inhibition is greater than might be expected given 28 that interneuron loss is relatively modest in Dlx1 mice. Here we report that voltage-clamp 29 recordings of CA1 interneurons in hippocampal slices prepared from Dlx1 animals older than 30 postnatal day 30 (>P30) revealed a significant reduction in excitatory postsynaptic current 31 (EPSC) amplitude. No changes in EPSCs onto interneurons were observed in cells recorded from 32 younger animals (P9-P12). Current-clamp recordings from interneurons at these early postnatal 33 ages showed that interneurons in Dlx1 mutants were immature and more excitable, although 34 membrane properties normalized by P30. TUNEL, caspase-3, and NeuN staining did not reveal 35 frank cell damage or loss in area CA3 of hippocampal sections from adult Dlx1 mice. Delayed 36 interneuron maturation may lead to interneuron hyperexcitability, followed by a compensatory 37 reduction in the strength of excitatory transmission onto interneurons. This reduced excitation 38 onto surviving interneurons, coupled with the loss of a significant fraction of GABAergic inputs 39 to excitatory neurons starting at P30, may underlie cortical dysrhythmia and seizures previously 40 observed in adult Dlx1 mice. 41