title: Characterization of inhibitory circuits in the malformed hippocampus of Lis1 mutant mice.
abstract: Heterozygous mutation or deletion of a lissencephaly gene (Lis1) in humans is associated with a severe disruption of cortical and hippocampal lamination, cognitive deficit, and severe seizures. Mice with one null allele of Lis1 (Lis1(+/-) mice) exhibit significant brain malformations and slowed migration of interneuron precursors. Although hyperexcitability was demonstrated in dysplastic hippocampal slices from Lis1(+/-) mice, little is known about synaptic function in these animals. Here we analyzed GABA-mediated synaptic inhibition. We recorded isolated whole cell inhibitory postsynaptic currents (IPSCs) on visually identified pyramidal neurons in disorganized CA1 regions of hippocampal slices prepared from Lis1(+/-) mice. We observed a 32% increase in spontaneous IPSC frequency in Lis1(+/-) mice compared with normotopic CA1 pyramidal neurons in age-matched controls. This increase was not associated with a change in spontaneous IPSC decay or miniature IPSC frequency. Mean IPSC amplitude was increased, and event histograms indicated a greater number of large (>125 pA) events. Tonic inhibition, response to paired-pulse stimulation and evoked IPSC decay kinetics were not altered. Consistent with increased synaptic inhibition, Lis1(+/-) interneurons also exhibited more spontaneous firing in cell-attached recordings and increased excitation as measured by voltage-clamp recording of spontaneous excitatory postsynaptic currents (EPSCs) onto interneurons. Our results reveal a significant alteration in the function of inhibitory circuits within the malformed Lis1(+/-) hippocampus. Given that precisely coordinated GABAergic activity is vital to generation of oscillatory activity and place field precision in hippocampus, these alterations in synaptic inhibition may contribute to seizures and altered cognitive function in type I Lissencephaly.
authors: Department of Neurological Surgery, University of California, San Francisco, Box 0520, 533 Parnassus Ave., San Francisco, CA 94143, USA.
authors: Daniel L
authors: DL
authors: Jones
authors: Scott C
authors: SC
authors: Baraban
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000235:genetics*; D000818:Animals; D000831:Animals, Newborn; D004558:Electric Stimulation / Q000379:methods; D006624:Hippocampus / Q000002:abnormalities* / Q000503:physiopathology; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000235:genetics*; D007395:Interneurons / Q000502:physiology; D051379:Mice; D008817:Mice, Mutant Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics*; D009154:Mutation / Q000502:physiology*; D009415:Nerve Net / Q000503:physiopathology*; D009433:Neural Inhibition / Q000235:genetics*; D018408:Patch-Clamp Techniques; D017966:Pyramidal Cells / Q000503:physiopathology
chemical_list: D008869:Microtubule-Associated Proteins; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase; C513190:Pafah1b1 protein, mouse