Impaired synaptic plasticity in a rat model of tuberous sclerosis.
Tuberous sclerosis complex (TSC) is a common hereditary disorder caused by mutations in either the TSC1 or TSC2 genes, and characterized by severe epilepsy, cerebral hamartomas and mental retardation. We have used rats that are heterozygous for an autosomal-dominant germline mutation in the TSC2 gene (TSC2+/- rats) to examine the consequences of TSC2 mutations for hippocampal synaptic plasticity. While basal synaptic transmission in the Schaffer collateral-CA1 synapse was not altered, paired-pulse plasticity was significantly enhanced in TSC2+/- rats (interpulse intervals 20-200 ms). Moreover, TSC2+/- rats exhibited a marked reduction of different forms of synaptic plasticity. Long-term potentiation (LTP) elicited following high-frequency tetanization of Schaffer collaterals was significantly decreased from 1.45 +/- 0.05-fold potentiation to 1.15 +/- 0.04 (measured after 60 min). This difference in LTP levels between TSC2+/- and wild-type rats also persisted in the presence of the gamma-aminobutyric acid (GABA)(A) receptor antagonist bicuculline. In addition to changed LTP, the level of long-term depression (LTD) elicited by different forms of low-frequency stimulation was significantly less in TSC2+/- rats. These results suggest that TSC2 mutations may cause hippocampal synapses to lose much of their potential for activity-dependent synaptic modification. An understanding of the underlying molecular pathways may suggest new therapeutic approaches aimed at inhibiting the development of the profound mental retardation in TSC.
Department of Epileptology, University of Bonn Medical Center, Sigmund-Freud-Strasse 25, 53105 Bonn, Germany.
Christian
C
von der Brelie
Robert
R
Waltereit
Lian
L
Zhang
Heinz
H
Beck
Timo
T
Kirschstein
D000818:Animals; D030801:Animals, Genetically Modified; D001640:Bicuculline / Q000494:pharmacology; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004558:Electric Stimulation / Q000379:methods; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D018756:GABA Antagonists / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D018408:Patch-Clamp Techniques / Q000379:methods; D051381:Rats; D020318:Rats, Long-Evans; D013569:Synapses / Q000473:pathology* / Q000502:physiology; D014402:Tuberous Sclerosis / Q000473:pathology* / Q000503:physiopathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics
D018756:GABA Antagonists; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D001640:Bicuculline