Scn2a sodium channel mutation results in hyperexcitability in the hippocampus in vitro.
OBJECTIVE
To investigate in vitro, the cellular network activity of the hippocampus in Q54 mice that display spontaneous seizures because of a gain-of-function mutation of the Scn2a sodium channel gene.


METHODS
Extacellular recordings were obtained from CA1 and CA3 pyramidal neurons in hippocampal slices prepared from Q54 transgenic and nontransgenic littermates (WT) under physiologic conditions as well as during periods of orthodromic stimulation of the Schaffer collaterals. Cerebral spinal fluid samples were analyzed and cresyl violet histology of the hippocampus was conducted.


RESULTS
Increased spontaneous extracellular activity was found in both CA1 and CA3 regions of Q54 hippocampal slices. Q54 slices also demonstrated significantly greater spontaneous and afterdischarge activity as well as population spike amplitude and duration following tetanic stimulus in comparison to WT slices. Frequency analysis of tetanically stimulated recordings indicated high-frequency components (100 and 200 Hz) unique to Q45 slices. Analysis of cresyl violet histology supports healthy Q54 slices up to 10 weeks, while Q54 cerebral spinal fluid shows elevated osmolarity.


CONCLUSIONS
Evidence for hyperexcitability and increased synaptic efficacy in Q54 mice was found by observing spontaneous activity as well as evoked activity. Response to tetanic stimulation included unique high-frequency oscillations, and resulted in an increased population spike amplitude and duration. Histological assessment shows equivalent neuronal development in both experimental groups. The data support the hypothesis that modified Scn2a channels in Q54 mice result in network hyperexcitability of the hippocampus necessary for the development and maintenance of temporal lobe seizures.
Kile
Kara Buehrer
KB
Neural Engineering Center, Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Tian
Nan
N
Durand
Dominique M
DM
D000818:Animals; D048588:Benzoxazines; D002555:Cerebrospinal Fluid / Q000737:chemistry / Q000502:physiology; D004195:Disease Models, Animal; D004558:Electric Stimulation / Q000379:methods; D004569:Electroencephalography / Q000706:statistics & numerical data; D004573:Electrolytes / Q000134:cerebrospinal fluid; D004833:Epilepsy, Temporal Lobe / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005071:Evoked Potentials / Q000502:physiology; D005110:Extracellular Space / Q000502:physiology; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense / Q000235:genetics*; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000502:physiology; D009994:Osmolar Concentration; D010078:Oxazines; D017966:Pyramidal Cells / Q000473:pathology / Q000503:physiopathology; D015222:Sodium Channels / Q000235:genetics* / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology
D048588:Benzoxazines; D004573:Electrolytes; D062551:NAV1.2 Voltage-Gated Sodium Channel; D009419:Nerve Tissue Proteins; D010078:Oxazines; C000654500:Scn2a protein, mouse; D015222:Sodium Channels; C028911:cresyl violet