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

Purpose: The murine homeobox-containing Otx gene is required for correct ne rvous system and sense organ development. Otx1(-/-) mice obtained by replac ing Otx with the lac Z gene show developmental abnormalities of the cerebel lum. mesencephalon, and cerebral cortex associated with spontaneous epilept ic seizures (1). The epileptogenic mechanisms accounting for these seizures were investigated by means of electrophysiological recordings made from ne ocortical slices. Methods: The 400-mu m slices were prepared from the somato-sensory cortex o f Otx1(-/-) and Otx1(+/+) mice, and the current clamp intracellular recordi ngs were obtained from layer V pyramidal neurons by means of pipettes conta ining K+ acetate 1.5 mol/L and biocytin 2% (pH 7.3). Results: Synaptic responses could be evoked in the neocortical pyramidal ne urons by electrically stimulating the underlying white matter. gamma-Aminob utyric acid A/B-mediated inhibitory postsynaptic potentials were more prono unced in the Otx1(-/-) than in the control pyramidal neurons from the earli est postnatal period; multisynaptic excitatory postsynaptic: potentials wer e 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 l ead to a hyperexcitable condition that is responsible for the epileptic man ifestations occurring in Otx1(-/-) mice. This excess of excitation is not c ounteracted 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 Otx 1(-/-) neocortex may lead to the excitatory hyperinnervation of layer V pyr amidal neurons.