Inhibitory Inputs to Hippocampal Interneurons Are Reorganized in Lis1 Mutant Mice

Graduate Program in Neuroscience and Epilepsy Research Laboratory, Department of Neurological Surgery, University of California San Francisco, San Francisco, California Submitted 5 May 2009; accepted in final form 8 June 2009 Epilepsy and brain malformation are commonly associated with excessive synaptic excitation and decreased synaptic inhibition of principal neurons. However, few studies have examined the state of synaptic inhibition of interneurons in an epileptic, malformed brain. We analyzed inhibitory inputs, mediated by -aminobutyric acid (GABA), to hippocampal interneurons in a mouse model of type 1 lissencephaly, a neurological disorder linked with severe seizures and brain malformation. In the disorganized hippocampal area CA1 of Lis1 +/– mice, we initially observed a selective displacement of fast-spiking, parvalbumin-positive basket-type interneurons from stratum oriens (SO) locations to s. radiatum and s. lacunosum-moleculare (R/LM). Next, we recorded spontaneous and miniature inhibitory postsynaptic currents (sIPSCs and mIPSCs) onto visually identified interneurons located in SO or R/LM of Lis1 +/– mice and age-matched littermate controls. We observed significant, layer-specific reorganizations in GABAergic inhibition of interneurons in Lis1 mutant mice. Spontaneous IPSC frequency onto SO interneurons was significantly increased in hippocampal slices from Lis1 +/– mice, whereas mIPSC mean amplitude onto these interneurons was significantly decreased. In addition, the weighted decay times of sIPSCs and mIPSCs were significantly increased in R/LM interneurons. Taken together, these findings illustrate the extensive redistribution and reorganization of inhibitory connections between interneurons that can take place in a malformed brain. Address for reprint requests and other correspondence: D. L. Jones, Department of Neurological Surgery, University of California, San Francisco, Box 0520, 533 Parnassus Ave., San Francisco, CA 94143 (E-mail: daniel.jones{at}ucsf.edu )