Cortical alterations in a model for absence epilepsy and febrile seizures: in vivo findings in mice carrying a human GABA(A)R gamma2 subunit mutation.
Childhood absence epilepsy (CAE) is one of the most common forms of epilepsy among children. The study of a large Australian family demonstrated that a point mutation in the gene encoding the gamma2 subunit of the GABA(A) receptor (G2R43Q) leads to an autosomal dominantly inherited form of CAE and febrile seizures (FS). In a transgenic mouse model carrying the gamma2 (R43Q) mutation heterozygous animals recapitulate the human phenotype. In-vitro experiments indicated that this point mutation impairs cortical inhibition and thus increases the likelihood of seizures. Here, using whole-cell (WC) and extracellular (EC) recordings as well as voltage-sensitive dye imaging (VSDI), we systematically searched for an in vivo correlate of cortical alterations caused by the G2R43Q mutation, as suggested by the mentioned in vitro results. We measured spontaneous and whisker-evoked activity in the primary somatosensory cortex and ventral posteriomedial nucleus of the thalamus (VPM) before and after intraperitoneal injection of the ictogenic substance pentylenetetrazol (PTZ) in urethane-anesthetized G2R43Q mice and controls in a blinded setting. Compared to wildtype controls in G2R43Q mice after PTZ injection we found 1.) Increased cortical spontaneous activity in layer 2/3 and layer 5/6 pyramidal neurons (increased standard deviation of the mean membrane potential in WC recordings), 2.) Increased variance of stimulus evoked cortical responses in VSDI experiments. 3.) The cortical effects are not due to increased strength or precision of thalamic output. In summary our findings support the hypothesis of a cortical pathology in this mouse model of human genetic absence epilepsy. Further study is needed to characterize underlying molecular mechanisms.
Department of Cell Physiology, Max-Planck-Institute for Medical Research, 69120 Heidelberg, Germany; Department of Neurology, Columbia University College of Physicians and Surgeons, NY, USA. Electronic address: JensJulianWitsch@gmail.com.
Jens
J
Witsch
Department of Cell Physiology, Max-Planck-Institute for Medical Research, 69120 Heidelberg, Germany; Department of Neurology, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany.
Daniel
D
Golkowski
Department of Psychiatry and Systems Neurophysiology Group, Central Institute of Mental Health, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany.
Thomas T G
TT
Hahn
Florey Neuroscience Institutes, University of Melbourne, Parkville, Victoria, Australia.
Steven
S
Petrou
Department of Cell Physiology, Max-Planck-Institute for Medical Research, 69120 Heidelberg, Germany; Department of Neuropaediatrics, University Hospital Giessen, Feulgenstraße 10-12, 35392 Gießen, Germany.
Hartwig
H
Spors
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D002540:Cerebral Cortex / Q000473:pathology*; D003292:Convulsants / Q000633:toxicity; D004195:Disease Models, Animal; D004832:Epilepsy, Absence / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics*; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D010433:Pentylenetetrazole / Q000633:toxicity; D011963:Receptors, GABA-A / Q000235:genetics*; D003294:Seizures, Febrile / Q000139:chemically induced / Q000235:genetics / Q000473:pathology*; D018709:Statistics, Nonparametric; D014738:Vibrissae / Q000294:innervation; D056969:Voltage-Sensitive Dye Imaging
D003292:Convulsants; D011963:Receptors, GABA-A; D010433:Pentylenetetrazole
Electrophysiology; Epilepsy; GABA; Voltage-sensitive dye imaging