Synaptic properties of neocortical neurons in epileptic mice lacking the Otx1 gene

Purpose: The murine homeobox-containing Otx gene is required for correct nervous system and sense organ development. Otx1(-/-) mice obtained by replacing Otx with the lac Z gene show developmental abnormalities of the cerebellum. mesencephalon, and cerebral cortex associated with spontaneous epileptic seizures (1). The epileptogenic mechanisms accounting for these seizures were investigated by means of electrophysiological recordings made from neocortical slices. Methods: The 400-mu m slices were prepared from the somato-sensory cortex of Otx1(-/-) and Otx1(+/+) mice, and the current clamp intracellular recordings were obtained from layer V pyramidal neurons by means of pipettes containing K+ acetate 1.5 mol/L and biocytin 2% (pH 7.3). Results: Synaptic responses could be evoked in the neocortical pyramidal neurons by electrically stimulating the underlying white matter. gamma-Aminobutyric acid A/B-mediated inhibitory postsynaptic potentials were more pronounced in the Otx1(-/-) than in the control pyramidal neurons from the earliest postnatal period; multisynaptic excitatory postsynaptic: potentials were significantly more expressed in the Otx1(-/-) mice also at the end of the first postnatal month, when they were only rarely encountered in controls. Conclusion: Excessive excitatory amino acid-mediated synaptic driving may lead to a hyperexcitable condition that is responsible for the epileptic manifestations occurring in Otx1(-/-) mice. This excess of excitation is not counteracted by well-developed gamma-aminobutyric acid activity, which seems to be involved in the synchronization of cell discharges. Our ongoing and more extensive comparative analysis of the mutants and controls should help to clarify the way in which the putative rearrangement taking place in Otx1(-/-) neocortex may lead to the excitatory hyperinnervation of layer V pyramidal neurons.