The epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph (mceph/mceph) is homozygous for a spontaneous mutation truncating the Shaker-like voltage gated potassium channel, Kv1.1 (Kcna1). The mceph/mceph mice are asymptomatic at birth, but develop from 3 weeks of age epileptic seizures, overgrowth and neuronal hyperplasia of the hippocampus. Hippocampal cognitive function of the mice was examined by investigating emotional memory using the aversive Passive Avoidance (PA) task combined with studies of explorative behavior using the non-aversive Novel Cage test (NCT). The behavioural results were examined by multivariate analysis. Compared to wild type and heterozygous mice, the mceph/mceph mice displayed lower exploratory and safety assessment behavior in the NCT and impairment in PA retention 24 hours after training, indicating an impairment in cognitive functions. In conclusion, the epileptic mouse model BALB/cByJ-Kv1.1mceph/mceph, with chronic epilepsy related to potassium-channelopathy, display a behavioural phenotype characterized by impairments in emotional memory and defensive motivational responses probably related to hippocampal dysfunctions.
J. F. van Brederode, J. M. Rho, R. Cerne, B. L. Tempel and W. J. Spain, “Evidence of Altered Inhibition in Layer V Pyramidal Neurons from Neocortex of Kcna1-Null Mice,” Neuroscience, Vol. 103, No. 4, 2001, pp. 921-929. doi:10.1016/S0306-4522(01)00041-0
V. Lopantsev, B. L. Tempel and P. A. Schwartzkroin, “Hyperexcitability of CA3 Pyramidal Cells in Mice Lacking the Potassium Channel Subunit Kv1.1,” Epilepsia, Vol. 44, No. 12, 2003, pp. 1506-1512. doi:10.1111/j.0013-9580.2003.44602.x
H. M. Brew, J. L. Hallows and B. L.Tempel, “Hyperexcitability and Reduced Low Threshold Potassium Currents in Auditory Neurons of Mice Lacking the Channel Subunit Kv1.1,” Journal of Physiology, Vol. 548, 2003, pp. 1-20. doi:10.1113/jphysiol.2002.035568
S. M. Zuberi, L. H. Eunson, A. Spauschus, R. De Silva, J. Tolmie, N. W. Wood, R. C. McWilliam, J. B. Stephenson, D. M. Kullmann and M. G. Hanna, “A Novel Mutation in the Human Voltage-Gated Potassium Channel Gene (Kv1.1) Associates with Episodic Ataxia Type 1 and Sometimes with Partial Epilepsy,” Brain, Vol. 122, No. 5, 1999, pp. 817-825. doi:10.1093/brain/122.5.817
L. H. Eunson, R. Rea, S. M. Zuberi, S. Youroukos, C. P. Panayiotopoulos and R. Liguori, “Clinical, Genetic, and Expression Studies of Mutations in the Potassium Channel Gene KCNA1 Reveal New Phenotypic Variability,” Annals of Neurology, Vol. 48, No. 4, 2000, pp. 647-656. doi:10.1002/1531-8249(200010)48:4 3.0.CO;2-Q
A. S. Persson, G. Klement, M. Almgren, K. Sahlholm, J. Nilsson, S. Petersson, P. ?rhem, M. Schalling and C. Lavebratt, “A Truncated Kv1.1 Protein in the Brain of the Megencephaly Mouse: Expression and Interaction,” BMC Neuroscience, Vol. 6, 2005, p. 65. doi:10.1186/1471-2202-6-65
S. Petersson, A.S. Persson, J. Johansen, M. Ingvar, M. Schalling and C. Lavebratt, “Truncation of the Shaker-Like Voltage-Gated Potassium Channel, Kv1.1, Causes Megencephaly,” European Journal of Neuroscience, Vol. 18, No. 12, 2003, pp. 3231-3240. doi:10.1111/j.1460-9568.2003.03044.x
S. L. Smart, V. Lopantsev, C. L. Zhang, C. A. Robbins, H. Wang, S. Y. Chiu, P. A. Schwartzkroin, A. Messing and B. L. Tempel, “Deletion of the Kv1.1 Potassium Channel Causes Epilepsy in Mice,” Neuron, Vol. 20, No. 4, 1998, pp. 809-819. doi:10.1016/S0896-6273(00)81018-1
A. Gambardella, A. Labate, A. Giallonardo and U. Aguglia, “Familial Mesial Temporal Lobe Epilepsies: Clinical and Genetic Features,” Epilepsia, Vol. 50, Suppl. 5, 2009, pp. 55-57. doi:10.1111/j.1528-1167.2009.02123.x
S. Jessberger, B. R?mer, H. Babu and G. Kempermann, “Seizures Induce Proliferation and Dispersion of Doublecortin-Positive Hippocampal Progenitor Cells,” Experimental Neurology, Vol. 196, No. 2, 2005, pp. 342-351. doi:10.1016/j.expneurol.2005.08.010
S. Petersson, C. Lavebratt, M. Schalling and T. H?kfelt, “Expression of Cholecystokinin, Enkephalin, Galanin and Neuropeptide Y Is Markedly Changed in the Brain of the Megencephaly Mouse,” Neuroscience, Vol. 100, No. 29, 2000, pp. 297-317. doi:10.1016/S0306-4522(00)00285-2
M. Diez, P. Schweinhardt, S. Petersson, F.-H. Wang, C. Lavebratt, M. Schalling, M., T. H?kfelt and C. Spenger, “MRI and in Situ Hybridization Reveal Early Disturbances in Cerebral Size and Gene Expression in the Megencephalic (mceph/mceph) Mouse,” European Journal of Neuroscience, Vol. 18, No. 12, 2003, pp. 3218-3230. doi:10.1111/j.1460-9568.2003.02994.x
A. S. Persson, E. Westman, F.-H. Wang, F. H. Khan, C. Spenger and C. Lavebratt, “Kv1.1 Null Mice Have Enlarged Hippocampus and Ventral Cortex,” BMC Neuroscience, Vol. 8, 2007, p. 10. doi:10.1186/1471-2202-8-10
M. Almgren, A. S. Persson, C. Fenghua, B. M. Witgen, M. Schalling, J. R. Nyengaard and C. Lavebratt, “Lack of Potassium Channel Induces Proliferation and Survival Causing Increased Neurogenesis and Two-Fold Hippocampus Enlargement,” Hippocampus, Vol. 17, No. 4, 2007, pp. 292-304. doi:10.1002/hipo.20268
M. Almgren, M. Schalling and C. Lavebratt, “Idiopathic Megalencephaly-Possible Cause and Treatment Opportunities: From Patient to Lab,” European Journal of Paediatric Neurology, Vol. 1, No. 26, 2008, pp. 438-445. doi:10.1016/j.ejpn.2007.11.008
E. D. Burg, C. V. Remillard and J. X. Yuan, “K + Channels in Apoptosis,” The Journal of Membrane Biology, Vol. 209, No. 1, 2006, pp. 3-20. doi:10.1007/s00232-005-0838-4
M. Lynch, U. Sayin, J. Bownds, S. Janumpalli and T. Sutula, “Long-Term Consequences of Early Postnatal Seizures on Hippocampal Learning and Plasticity,” European Journal of Neuroscience, Vol. 12, No. 7, 2000, pp. 2252-2264. doi:10.1046/j.1460-9568.2000.00117.x
C. J. Müller, I. Gr?ticke, M. Bankstahl and W. L?scher, “Behavioral and Cognitive Alterations, Spontaneous Seizures, and Neuropathology Developing after a Pilocarpine-Induced Status Epilepticus in C57BL/6 Mice,” Experimental Neurology, Vol. 219, No. 1, 2009, pp. 284-297. doi:10.1016/j.expneurol.2009.05.035
I. Gr?ticke, K. Hoffmann and W. L?scher, “Behavioral Alterations in a Mouse Model of Temporal Lobe Epilepsy in Mice Induced by Intrahippocampal Injection of Kainite,” Experimental Neurology, Vol. 213, No. 1, 2008, pp. 71-83. doi:10.1016/j.expneurol.2008.04.036
M. C?rreno, A. Donaire and R. Sánchez-Carpintero, “Cognitive Disorders Associated with Epilepsy: Diagnosis and Treatment,” Neurologist, Vol. 14, No. 6, 2008, pp. S26-S34. doi:10.1097/01.nrl.0000340789.15295.8f
J. E. LeDoux, “Emotional Memory Systems in the Brain,” Behavioural Brain Research, Vol. 58, No. 1-2, 1993, pp. 69-79. doi:10.1016/0166-4328(93)90091-4
R. G. Morris, “Developments of a Water-Maze Procedure for Studying Spatial Learning in the Rat,” Journal of Neu roscience Methods, Vol. 11, No. 1, 1984, pp. 47-60. doi:10.1016/0165-0270(84)90007-4
B. Milner, L. R. Squire and E. R. Kandel, “Cognitive Neuroscience and the Study of Memory,” Neuron, Vol. 20, No. 3, 1998, pp. 445-468. doi:10.1016/S0896-6273(00)80987-3
S. O. ?gren, T. M. Eriksson, E. Elvander-Tottie, C. D’Addario, J. C. Ekstr?m, P. Svenningsson, B. Meister, J. Kehr and O. Stiedl, “The Role of 5-HT(1A) Receptors in Learning and Memory,” Behavioural Brain Research, Vol. 195, No. 1, 2008, pp. 54-77. doi:10.1016/j.bbr.2008.02.023
B. P. Hermann, J. J. Lin, J. E. Jones and M. Seidenberg, “The Emerging Architecture of Neuropsychological Impairment in Epilepsy,” Neurologic Clinics, Vol. 27, No. 4, 2009, pp. 881-907. doi:10.1016/j.ncl.2009.08.001
C. Sgobio, V. Ghiglieri, C. Costa, V. Bagetta, S. Siliquini, I. Barone, M. Di Filippo, F. Gardoni, E. D. Gundelfinger, M. Di Luca, B. Picconi and P. Calabresi, “Hippocampal Synaptic Plasticity, Memory, and Epilepsy: Effects of Long-Term Valproic Acid Treatment,” Biological Psychiatry, Vol. 67, No. 6, 2010, pp. 567-574. doi:10.1016/j.biopsych.2009.11.008
L. R. Donahue, S. A. Cook, K. R. Johnson, R. T. Bronson and M. T. Davisson, “Megencephaly: A New Mouse Mutation on Chromosome 6 That Causes Hypertrophy of the Brain,” Mammalian Genome, Vol. 7, No. 12, 1996, pp. 871-876. doi:10.1007/s003359900259
H. Augustsson, K. Dahlborn and B. J. Meyerson, “Exploration and Risk Assessment in Female Wild House Mice (Mus Musculus Musculus) and Two Laboratory Strains,” Physiology & Behavior, Vol. 84, No. 2, 2005, pp. 265-277. doi:10.1016/j.physbeh.2004.12.002
P. J. Baarendse, G. van Grootheest, R. F. Jansen, A. W. Pieneman, S. O. ?gren, M. Verhage and O. Stiedl, “Differential Involvement of the Dorsal Hippocampus in Passive Avoidance in C57bl/6J and DBA/2J Mice,” Hippocampus, Vol. 18, No. 1, 2008,pp. 11-19. doi:10.1002/hipo.20356
B. L. Finlay and R. B. Darlington, “Linked Regularities in the Development and Evolution of Mammalian Brains,” Science, Vol. 268, No. 5217, 1995, pp. 1578-1584. doi:10.1126/science.7777856
N. Madjid, E. E. Tottie, M. Lüttgen, B. Meister, J. Sandin, A. Kuzmin, O. Stiedl, S. O. ?gren, “5-Hydroxytryptamine 1A Receptor Blockade Facilitates Aversive Learning in Mice: Interactions with Cholinergic and Glutamatergic Mechanisms,” The Journal of Pharmacology and Experimental Therapeutics, Vol. 316, No. 2, 2006, pp. 581-591. doi:10.1124/jpet.105.092262
T. M. Eriksson, N. Madjid, E. Elvander-Tottie, O. Stiedl, P. Svenningsson and S. O. ?gren, “Blockade of 5-HT 1B Receptors Facilitates Contextual Aversive Learning in Mice by Disinhibition of Cholinergic and Glutamatergic Neurotrans-Mission,” Neuropharmacology, Vol. 54, No. 7, 2008, pp. 1041-1050. doi:10.1016/j.neuropharm.2008.02.007
O. Stiedl, I. Misane, P. Tovote, A. Ronnenberg, J. Spiess and S. O. ?gren, “Involvement of NMDA Receptors in the Dorsal Hippocampus in Passive Avoidance Learning in Mice,” Society for Neuroscience Abstract, Vol. 773, 2004, p. 12.
J. M. Marques, I. A. Olsson, S. O. ?gren and K. Dahlborn, “Evaluation of Exploration and Risk Assessment in Pre-Weaning Mice Using the Novel Cage Test,” Physiology & Behavior, Vol. 93, No. 1-2, 2008, pp. 139-147. doi:10.1016/j.physbeh.2007.08.006
E. B. Ottoni, “EthoLog 2.2: A Tool for the Transcription and Timing of Behavior Observation Sessions,” Behavior Research Methods, Instruments, & Computers, Vol. 32, No. 3, 2000, pp. 446-449. doi:10.3758/BF03200814
K. Franklin and G. Paxinos, “The Mouse Brain in Stereotaxic Coordinates,” Academic Press, San Diego, 1997.
E. ?berg, C. P. Hofstetter, L. Olson and S. Brené, “Moderate Ethanol Consumption Increases Hippocampal Cell Proliferation and Neurogenesis in the Adult Mouse,” International Journal of Neuropsychopharmacology, Vol. 8 No. 4, 2005, pp. 557-567. doi:10.1017/S1461145705005286
M. J. West and H. J. Gundersen, “Unbiased Stereological Estimation of the Number of Neurons in the Human Hippocampus,” Journal of Comparative Neurology, Vol. 296, No. 1, 1990, pp. 1-22. doi:10.1002/cne.902960102
J. E. Jackson, “A User’s Guide to Principal Components,” John Wiley & Sons Inc, New York, 1991. doi:10.1002/0471725331
E. Roman and G. Colombo, “Lower Risk Taking and Exploratory Behavior in Alcohol-Preferring sP Rats than in Alcohol Non-Preferring sNP Rats in the Multivariate Concentric Square Field (MCSF) Test,” Behavioural Brain Research, Vol. 205, No. 1, 2009, pp. 249-58. doi:10.1016/j.bbr.2009.08.020
A. R. Giovagnoli and G. Avanzini, “Quality of Life and Memory Performance in Patients with Temporal Lobe EpilLepsy,” Acta Neurologica Scandinavica, Vol. 101, No. 5, 2000, pp. 295-300. doi:10.1034/j.1600-0404.2000.90257a.x
U. Hlobil, C. Rathore, A. Alexander, S. Sarma and K. Radhakrishnan, “Impaired Facial Emotion Recognition in Patients with Mesial Temporal Lobe Epilepsy Associated with Hippocampal Sclerosis (MTLE-HS): Side and Age at Onset Matters,” Epilepsy Research, Vol. 80, No. 2-3, 2008, pp. 150-157.
V. Tuchscherer, M. Seidenberg, D. Pulsipher, M. Lancaster, L. Guidotti and B. Hermann, “Extrahippocampal Integrity in Temporal Lobe Epilepsy and Cognition: Thalamus and Executive Functioning,” Epilepsy & Behaviour, Vol. 17, No. 4, 2010, pp. 478-482. doi:10.1016/j.yebeh.2010.01.019
C. M. Gray and W. Singer, “Stimulus-Specific Neuronal Oscillations in Orientation Columns of Cat Visual Cortex,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 86, No. 5, 1989, pp. 1698-1702.
A. K. Engel and W. Singer, “Temporal Binding and the Neural Correlates of Sensory Awareness,” Trends in Cognitive Sciences, No. 5, No. 1, 2001, pp. 16-25.
K. Jakubs, A. Nanobashvili, S. Bonde, C. T. Ekdahl, Z. Kokaia, M. Kokaia and O. Lindvall, “Environment Matters: Synaptic Properties of Neurons Born in the Epileptic Adult Brain Develop to Reduce Excitability,” Neuron, Vol. 52, No. 6, 2006, pp. 1047-1059. doi:10.1016/j.neuron.2006.11.004
L. S. Overstreet-Wadiche, D. A. Bromberg, A. L. Bensen and G. L. Westbrook, “Seizures Accelerate Functional Integration of Adult-Generated Granule Cells,” The Journal of Neuroscience, Vol. 26, No. 15, 2006, pp. 4095-4103. doi:10.1523/JNEUROSCI.5508-05.2006
S. Jessberger, C. Zhao, N. Toni, G. D. Clemenson, Y. Li, and F. H. Gage, “Seizure-Associated, Aberrant Neurogenesis in Adult Rats Characterized with Retrovirus-Mediated Cell Labelling,” The Journal of Neuroscience, Vol. 29, No. 35, 2007, pp. 9400-9407.
B. Steiner, S. Zurborg, H. H?rster, K. Fabel and G. Kempermann, “Differential 24 h Responsiveness of Prox1-Expressing Precursor Cells in Adult Hippocampal Neurogenesis to Physical Activity, Environmental Enrichment, and Kainic Acid-Induced Seizures,” Neuroscience, Vol. 154, No. 2, 2008, pp. 521-529. doi:10.1016/j.neuroscience.2008.04.023
J. M. Koolhaas, S. F. de Boer, B. Buwalda and K. van Reenen, “Individual Variation in Coping with Stress: A Multi-Dimensional Approach of Ultimate and Proximate Mechanisms,” Brain, Behavior and Evolution, Vol. 70, No. 4, 2007, pp. 218-226. doi:10.1159/000105485
I. Gr?ticke, K. Hoffmann and W. L?scher, “Behavioral Alterations in the Pilocarpine Model of Temporal Lobe Epilepsy in Mice,” Experimental Neurology, Vol. 207, No. 2, 2007, pp. 329-349. doi:10.1016/j.expneurol.2007.06.021
B. M. Spruijt, J. A. van Hooff and W. H. Gispen, ”Ethology and Neurobiology of Grooming Behaviour,” Physiological Reviews, Vol. 72, No. 3, 1992, pp. 825-852.