Disruption of PLC-beta 1-mediated signal transduction in mutant mice causes age-dependent hippocampal mossy fiber sprouting and neurodegeneration.
Aberrant reorganization of hippocampal mossy fibers occurs in human temporal lobe epilepsy and rodent epilepsy models. We generated a mouse model showing massive late-onset aberrant mossy fiber sprouting in the adult hippocampus. The mutation in this mouse model derives from an intronic insertion of transgene DNA in the mouse PLC-beta1 gene (PLC-beta 1(-/-)(TC) mutation) leading to a splice mutation of the PLC-beta 1 gene and a complete loss of downstream PLC-beta 1 expression. PLC-beta 1(-/-)(TC) mutants develop a loss of NMDA-receptors in the stratum oriens of region CA1, apoptotic neuronal death, and reduced hippocampal PKC activity. The phenotype of these mice further consists of a late-onset epileptiform hyperexcitability, behavioral modifications in a radial maze and in an open field, female nurturing defect, and male infertility. In the present study, we provide evidence that the arising of the behavioral phenotype in PLC-beta 1(-/-)(TC) mice correlates in time with the development of the aberrant mossy fiber projections and that the disruption of the PLC-beta 1-mediated signal transduction pathway may lead to a functional cholinergic denervation, which could cause hippocampal remodeling and, in consequence, epileptiform hyperexcitability.
Böhm
Detlef
D
Institute of Human Genetics, University of Göttingen, Heinrich-Düker-Weg 12, 37073 Göttingen, Germany.
Schwegler
Herbert
H
Kotthaus
Lisa
L
Nayernia
Karim
K
Rickmann
Michael
M
Köhler
Michael
M
Rosenbusch
Joachim
J
Engel
Wolfgang
W
Flügge
Gabriele
G
Burfeind
Peter
P
D000375:Aging / Q000235:genetics* / Q000378:metabolism; D017398:Alternative Splicing / Q000235:genetics; D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D002874:Chromosome Mapping; D004195:Disease Models, Animal; D004833:Epilepsy, Temporal Lobe / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D005260:Female; D020439:Growth Cones / Q000201:enzymology; D007527:Isoenzymes / Q000172:deficiency* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008818:Mice, Neurologic Mutants; D019599:Mossy Fibers, Hippocampal / Q000201:enzymology* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D009410:Nerve Degeneration / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D009473:Neuronal Plasticity / Q000235:genetics; D054799:Phospholipase C beta; D011493:Protein Kinase C / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics*; D019076:Transgenes / Q000235:genetics; D010738:Type C Phospholipases / Q000172:deficiency* / Q000235:genetics
D007527:Isoenzymes; D016194:Receptors, N-Methyl-D-Aspartate; D011993:Recombinant Fusion Proteins; D002217:Carbachol; D011493:Protein Kinase C; D010738:Type C Phospholipases; C518033:PLCB1 protein, human; D054799:Phospholipase C beta; C518034:Plcb1 protein, mouse