The impact of genetic background on neurodegeneration and behavior in seizured mice

We used pilocarpine‐induced seizures in mice to determine the impact of genetic background on the vulnerability of hippocampal neurons and associated changes of behavioral performance. The susceptibility of hippocampal neurons to seizure‐induced cell death paralleled the severity of the seizures and depended on genetic background. Hippocampal neurons in C57BL/6 mice were most resistant to cell death, whereas they were highly vulnerable in FVB/N mice. The degree of neuronal degeneration in F1 hybrid mice obtained by crossing the two strains was at an intermediate level between the parent strains. Two weeks after the severe seizures, performance in a water‐maze place navigation task showed a bimodal distribution. Seventeen of 19 (90%) F1 mice were completely unable to learn while the other two learned reasonably well. Of 28 C57BL/6 mice with similarly severe seizures, six were as strongly impaired as their F1 counterparts (22%). The remaining 22 performed normally, indicating a much lower probability of C57BL/6 mice to be affected. Treated mice showed a deficit of open‐field exploration which was strongly correlated with the impairment in the place navigation task and was again more severe in F1 mice. Our results show that the vulnerability of hippocampal neurons to pilocarpine‐induced seizures, as well as the associated behavioral changes, depended on genetic background. Furthermore, they confirm and extend our earlier finding that a relatively modest reduction of hippocampal cell death can be associated with dramatic changes of behavioral performance and emphasize the importance of tightly‐controlled genetic backgrounds in biological studies.

[1]  A. Zafar,et al.  Credentialing Organizations , 2022, The Neurodiagnostic journal.

[2]  B. Zörner,et al.  Forebrain-specific trkB-receptor knockout mice: behaviorally more hyperactive than “depressive” , 2003, Biological Psychiatry.

[3]  H. Lipp,et al.  Emotional instability but intact spatial cognition in adenosine receptor 1 knock out mice , 2003, Behavioural Brain Research.

[4]  David P. Wolfer,et al.  Does cAMP Response Element-Binding Protein Have a Pivotal Role in Hippocampal Synaptic Plasticity and Hippocampus-Dependent Memory? , 2003, The Journal of Neuroscience.

[5]  A. Akhmedov,et al.  Impaired explorative behavior and neophobia in genetically modified mice lacking or overexpressing the extracellular serine protease inhibitor neuroserpin , 2003, Molecular and Cellular Neuroscience.

[6]  R. Dingledine,et al.  Neuronal and glial pathological changes during epileptogenesis in the mouse pilocarpine model , 2003, Experimental Neurology.

[7]  P. Schauwecker.  Differences in ionotropic glutamate receptor subunit expression are not responsible for strain-dependent susceptibility to excitotoxin-induced injury. , 2003, Brain research. Molecular brain research.

[8]  H. Lipp,et al.  Intact spatial memory in mice with seizure-induced partial lossof hippocampal pyramidal neurons , 2003, Neurobiology of Disease.

[9]  R. Nitsch,et al.  Passive Immunization against β-Amyloid Peptide Protects Central Nervous System (CNS) Neurons from Increased Vulnerability Associated with an Alzheimer's Disease-causing Mutation* , 2002, The Journal of Biological Chemistry.

[10]  Y. Benjamini,et al.  Controlling the false discovery rate in behavior genetics research , 2001, Behavioural Brain Research.

[11]  Hans-Peter Lipp,et al.  Extended analysis of path data from mutant mice using the public domain software Wintrack , 2001, Physiology & Behavior.

[12]  George Paxinos,et al.  The Mouse Brain in Stereotaxic Coordinates , 2001 .

[13]  Ilan Golani,et al.  SEE: a tool for the visualization and analysis of rodent exploratory behavior , 2001, Neuroscience & Biobehavioral Reviews.

[14]  M. Avoli,et al.  Brain‐derived neurotrophic factor superinduction parallels anti‐epileptic−neuroprotective treatment in the pilocarpine epilepsy model , 2001, Journal of neurochemistry.

[15]  P. Schauwecker.  Seizure-induced neuronal death is associated with induction of c-Jun N-terminal kinase and is dependent on genetic background , 2000, Brain Research.

[16]  E. Borrelli,et al.  Neuroprotective Role of Dopamine Against Hippocampal Cell Death , 2000, The Journal of Neuroscience.

[17]  L. Velíšek,et al.  Neuroprotective Effects of Estrogens on Hippocampal Cells in Adult Female Rats After Status Epilepticus , 2000, Epilepsia.

[18]  A. Greenshaw,et al.  Effects of AMPA/kainate receptor blockade on responses to dopamine receptor agonists in the core and shell of the rat nucleus accumbens , 2000, Psychopharmacology.

[19]  M. Lazdunski,et al.  Polyunsaturated fatty acids are potent neuroprotectors , 2000, The EMBO journal.

[20]  M. Bennett,et al.  Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[21]  Tobias Bonhoeffer,et al.  Essential Role for TrkB Receptors in Hippocampus-Mediated Learning , 1999, Neuron.

[22]  Philippe P Roux,et al.  p75 Neurotrophin Receptor Expression Is Induced in Apoptotic Neurons After Seizure , 1999, The Journal of Neuroscience.

[23]  J. Barnes,et al.  Behavioural analysis and susceptibility to CNS injury of four inbred strains of mice , 1999, Brain Research.

[24]  A. Rice,et al.  Status Epilepticus Causes Long‐Term NMDA Receptor‐Dependent Behavioral Changes and Cognitive Deficits , 1998, Epilepsia.

[25]  R. Sankar,et al.  Patterns of Status Epilepticus-Induced Neuronal Injury during Development and Long-Term Consequences , 1998, The Journal of Neuroscience.

[26]  A. Levey,et al.  Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[27]  P. Rakic,et al.  Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene , 1997, Nature.

[28]  M Kokaia,et al.  Apoptosis and proliferation of dentate gyrus neurons after single and intermittent limbic seizures. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[29]  T. Schallert,et al.  Blind rats are not profoundly impaired in the reference memory Morris water maze and cannot be clearly discriminated from rats with cognitive deficits in the cued platform task. , 1997, Brain research. Cognitive brain research.

[30]  O. Steward,et al.  Genetic determinants of susceptibility to excitotoxic cell death: implications for gene targeting approaches. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[31]  S. Tonegawa,et al.  The Essential Role of Hippocampal CA1 NMDA Receptor–Dependent Synaptic Plasticity in Spatial Memory , 1996, Cell.

[32]  David J. Anderson,et al.  Subregion- and Cell Type–Restricted Gene Knockout in Mouse Brain , 1996, Cell.

[33]  K. I. Blum,et al.  Impaired Hippocampal Representation of Space in CA1-Specific NMDAR1 Knockout Mice , 1996, Cell.

[34]  R. Schwarcz,et al.  Preferential neuronal loss in layer III of the medial entorhinal cortex in rat models of temporal lobe epilepsy , 1995, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[35]  G. Simonian,et al.  A COMPARISON OF SURVIVAL AT DIFFERENT DEGREES OF HEMORRHAGIC SHOCK IN GERM-FREE AND GERM-BEARING RATS , 1995, Shock.

[36]  D. Fujikawa.  Neuroprotective Effect of Ketamine Administered After Status Epilepticus Onset , 1995, Epilepsia.

[37]  R. Sidman,et al.  PCR analysis of DNA from 70-year-old sections of rodless retina demonstrates identity with the mouse rd defect. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[38]  D. Choi.  Excitotoxic cell death. , 1992, Journal of neurobiology.

[39]  Wim E Crusio,et al.  Behavioral responses to novelty and structural variation of the hippocampus in mice. I. Quantitative-genetic analysis of behavior in the open-field , 1989, Behavioural Brain Research.

[40]  E. Cavalheiro,et al.  Only certain antiepileptic drugs prevent seizures induced by pilocarpine , 1987, Brain Research Reviews.

[41]  W. J. Brown,et al.  Temporal Lobe Volumetric Cell Densities in Temporal Lobe Epilepsy , 1984, Epilepsia.

[42]  W. J. Brown,et al.  Distribution of Pyramidal Cell Density and Hyperexcitability in the Epileptic Human Hippocampal Formation , 1984, Epilepsia.

[43]  Z. Bortolotto,et al.  Seizures produced by pilocarpine in mice: A behavioral, electroencephalographic and morphological analysis , 1984, Brain Research.

[44]  E. Cavalheiro,et al.  Limbic seizures produced by pilocarpine in rats: Behavioural, electroencephalographic and neuropathological study , 1983, Behavioural Brain Research.

[45]  R. Morris.  Spatial Localization Does Not Require the Presence of Local Cues , 1981 .

[46]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. 3. Mechanisms. , 1972, Electroencephalography and clinical neurophysiology.

[47]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[48]  J. R. Misanin,et al.  Visual perception in the retinal degenerate C3H mouse. , 1970, Journal of comparative and physiological psychology.

[49]  Rüdiger Klein,et al.  Long‐term monitoring of hippocampus‐dependent behavior in naturalistic settings: Mutant mice lacking neurotrophin receptor TrkB in the forebrain show spatial learning but impaired behavioral flexibility , 2002, Hippocampus.

[50]  K. I. Blum,et al.  Hippocampal CA1-region-restricted knockout of NMDAR1 gene disrupts synaptic plasticity, place fields, and spatial learning. , 1996, Cold Spring Harbor symposia on quantitative biology.

[51]  Hauser Wa.  Status epilepticus: frequency, etiology, and neurological sequelae. , 1983, Advances in neurology.

[52]  W. Hauser.  Status epilepticus: frequency, etiology, and neurological sequelae. , 1983, Advances in neurology.