Cellular anatomy, physiology and epileptiform activity in the CA3 region of Dcx knockout mice: a neuronal lamination defect and its consequences

Abstract

We report data on the neuronal form, synaptic connectivity, neuronal excitability and epileptiform population activities generated by the hippocampus of animals with an inactivated doublecortin gene. The protein product of this gene affects neuronal migration during development. Human doublecortin (DCX) mutations are associated with lissencephaly, subcortical band heterotopia, and syndromes of intellectual disability and epilepsy. In Dcx(-/Y) mice, CA3 hippocampal pyramidal cells are abnormally laminated. The lamination defect was quantified by measuring the extent of the double, dispersed or single pyramidal cell layer in the CA3 region of Dcx(-/Y) mice. We investigated how this abnormal lamination affected two groups of synapses that normally innervate defined regions of the CA3 pyramidal cell membrane. Numbers of parvalbumin (PV)-containing interneurons, which contact peri-somatic sites, were not reduced in Dcx(-/Y) animals. Pyramidal cells in double, dispersed or single layers received PV-containing terminals. Excitatory mossy fibres which normally target proximal CA3 pyramidal cell apical dendrites apparently contact CA3 cells of both layers in Dcx(-/Y) animals but sometimes on basilar rather than apical dendrites. The dendritic form of pyramidal cells in Dcx(-/Y) animals was altered and pyramidal cells of both layers were more excitable than their counterparts in wild-type animals. Unitary inhibitory field events occurred at higher frequency in Dcx(-/Y) animals. These differences may contribute to a susceptibility to epileptiform activity: a modest increase in excitability induced both interictal and ictal-like discharges more effectively in tissue from Dcx(-/Y) mice than from wild-type animals.