Temporal lobe epilepsy induces intrinsic alterations in Na channel gating in layer II medial entorhinal cortex neurons.
Temporal lobe epilepsy (TLE) is the most common form of adult epilepsy involving the limbic structures of the temporal lobe. Layer II neurons of the entorhinal cortex (EC) form the major excitatory input into the hippocampus via the perforant path and consist of non-stellate and stellate neurons. These neurons are spared and hyper-excitable in TLE. The basis for the hyper-excitability is likely multifactorial and may include alterations in intrinsic properties. In a rat model of TLE, medial EC (mEC) non-stellate and stellate neurons had significantly higher action potential (AP) firing frequencies than in control. The increase remained in the presence of synaptic blockers, suggesting intrinsic mechanisms. Since sodium (Na) channels play a critical role in AP generation and conduction we sought to determine if Na channel gating parameters and expression levels were altered in TLE. Na channel currents recorded from isolated mEC TLE neurons revealed increased Na channel conductances, depolarizing shifts in inactivation parameters and larger persistent (I(NaP)) and resurgent (I(NaR)) Na currents. Immunofluorescence experiments revealed increased staining of Na(v)1.6 within the axon initial segment and Na(v)1.2 within the cell bodies of mEC TLE neurons. These studies provide support for additional intrinsic alterations within mEC layer II neurons in TLE and implicate alterations in Na channel activity and expression, in part, for establishing the profound increase in intrinsic membrane excitability of mEC layer II neurons in TLE. These intrinsic changes, together with changes in the synaptic network, could support seizure activity in TLE.
Department of Anesthesiology, University of Virginia Health System, Charlottesville, VA 22908, USA.
Nicholas J
NJ
Hargus
Ellen C
EC
Merrick
Aradhya
A
Nigam
Christopher L
CL
Kalmar
Aparna R
AR
Baheti
Edward H
EH
Bertram
Manoj K
MK
Patel
D000818:Animals; D004195:Disease Models, Animal; D018728:Entorhinal Cortex / Q000378:metabolism* / Q000473:pathology; D004833:Epilepsy, Temporal Lobe / Q000378:metabolism* / Q000473:pathology; D015640:Ion Channel Gating / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009433:Neural Inhibition / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009924:Organ Culture Techniques; D051381:Rats; D017207:Rats, Sprague-Dawley; D015222:Sodium Channels / Q000502:physiology*; D013569:Synapses / Q000235:genetics
D015222:Sodium Channels