title: Inhibitory inputs to hippocampal interneurons are reorganized in Lis1 mutant mice.
abstract: 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 gamma-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.
authors.affiliation: Graduate Program in Neuroscience and Epilepsy Research Laboratory, Department of Neurological Surgery, University of California, San Francisco, San Francisco, California 94143, USA. daniel.jones@ucsf.edu
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Jones
authors.forename: Scott C
authors.initials: SC
authors.lastname: Baraban
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics* / Q000378:metabolism; D000200:Action Potentials; D000818:Animals; D064032:Calbindin 2; D054221:Classical Lissencephalies and Subcortical Band Heterotopias / Q000473:pathology* / Q000503:physiopathology*; D004195:Disease Models, Animal; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials; D007395:Interneurons / Q000502:physiology*; D008564:Membrane Potentials / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics* / Q000378:metabolism; D009434:Neural Pathways / Q000473:pathology / Q000503:physiopathology; D010320:Parvalbumins / Q000378:metabolism; D018408:Patch-Clamp Techniques; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism; D013997:Time Factors; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D064032:Calbindin 2; D008869:Microtubule-Associated Proteins; D010320:Parvalbumins; D064030:S100 Calcium Binding Protein G; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse