Potentially epileptogenic dysfunction of cortical NMDA‐ and GABA‐mediated neurotransmission in Otx1^–/– mice

Abstract

Knockout Otx1 mice present a microcephalic phenotype mainly due to reduced deep neocortical layers and spontaneous recurrent seizures. We investigated the excitable properties of layer V pyramidal neurons in neocortical slices prepared from Otx1-/- mice and age-matched controls. The qualitative firing properties of the neurons of Otx1-/- mice were identical to those found in wild-type controls, but the proportion of intrinsically bursting (IB) neurons was significantly smaller. This is in line with the lack of the Otx1 gene contribution to the generation and differentiation of neurons destined for the deep neocortical layers, in which IB neurons are located selectively in wild-type rodents. The pyramidal neurons recorded in Otx1-/- mice responded to near-threshold electrical stimulation of the underlying white matter, with aberrant polysynaptic excitatory potentials often leading to late action potential generation. When the strength of the stimulus was increased, the great majority of the Otx1-/- neurons (78%) responded with a prominent biphasic inhibitory postsynaptic potential that was significantly larger than that observed in the wild-type mice, and was often followed by complex postinhibitory depolarizing events. Both late excitatory postsynaptic potentials and postinhibitory excitation were selectively suppressed by NMDA receptor antagonists, but not by AMPA antagonists. We conclude that the cortical abnormalities of Otx1-/- neocortex due to a selective loss of large projecting neurons lead to a complex rearrangement of local circuitry, which is characterized by an excess of N-methyl-d-aspartate-mediated polysynaptic excitation that is counteracted by GABA-mediated inhibition in only a limited range of stimulus intensity. Prominent postsynaptic inhibitory potentials may also act as a further pro-epileptogenic event by synchronizing abnormal excitatory potentials.

Electrophysiological Abnormalities in Both Axotomized and Nonaxotomized Pyramidal Neurons following Mild Traumatic Brain Injury

“…To our knowledge, ours is the first report of a decrease in intrinsic bursting phenotype in a model of disease, although decreased numbers have been observed in a genetic model of neocortical malformation (Sancini et al, 2001). Intrinsic bursting behavior has been linked to an active depolarizing after-potential and underlying persistent Na + current (Nishimura et al, 2001; Azouz et al, 1996; Brumberg et al., 2000) and can be modified by A-type K + currents (Guatteo et al, 1996).…”

THE BIOLOGY OF EPILEPSY GENES

“…Genetic disruption of homeobox genes related to specification, regionalization, and terminal differentiation of the neocortex result in epileptic phenotypes. In a mutant mouse deleted for OTX-1 with spontaneous seizures, analysis of layer V cortical pyramidal neurons suggests that a selective loss of large projecting neurons leads to a complex rearrangement of local circuitry characterized by an excess of NMDA-mediated excitation (Sancini et al 2001). Also within this category, mutation of the human ARX gene is associated with a variable syndrome of myoclonic seizures, infantile spasms, and mental retardation types in a neurological syndrome featuring epilepsy and mental retardation (Stromme et al 2002).…”

The Association of OTX1 rs17850223 Polymorphisms in Han Chinese Patients with Idiopathic Epilepsy

“…The OTX1 gene encodes a member of the bicoid subfamily of homeodomain-containing transcription factors. The encoded protein acts as a transcription factor and might play a role in the brain and sensory organ development [15,16]. Early animal studies indicate that OTX1 null mice suffered from spontaneous epileptic seizures and exhibited abnormalities that primarily affected the entire dorsal telencephalic cortex with a more pronounced effect in the temporal and perirhinal areas [12,17].…”