Is Cognition Altered in the Eker Rat Model of Tuberous Sclerosis Complex?

Abstract

Enhanced Episodic-Like Memory and Kindling Epilepsy in a Rat Model of Tuberous SclerosisWaltereit R, Welzl H, Dichgans J, Lipp HP, Schmidt WJ, Weller MJ Neurochem 2006;96:407–413Tuberous sclerosis complex (TSC) is a common neurological autosomal-dominant syndrome caused by mutations in the TSC1 or TSC2 genes. TSC starts in early childhood and is characterized by cerebral hamartomas (benign tumours), severe epilepsy and cognitive deficits such as mental retardation and autism. The hamartomas are characterized by loss of the remaining wild-type TSC allele, and clinical data implicate cerebral hamartomas in the generation of epileptic seizures, which may play a significant role in the development of mental retardation. The TSC2 mutation predicts alterations in mitogen-associated protein kinase (MAPK) and, together with the TSC1 mutation, in mammalian target of rapamycin (mTOR) signalling pathways. Both pathways are involved in neuronal plasticity. We therefore hypothesized that the heterozygous mutation itself, besides cerebral hamartomas, contributes to the pathogenesis of cognitive deficits and possibly also epilepsy. Here, we show that young adult TSC2+/– rats, which are virtually free of cerebral hamartomas, exhibit enhanced episodic-like memory and enhanced responses to chemically induced kindling. The activation of cyclic adenosine monophosphate (cAMP) in the hippocampus results in stronger induction of phospho-p42-MAPK in TSC2+/– rats than in wild-type animals. Thus, the cognitive phenotype and, possibly, epilepsy in TSC patients may result not only from the focal hamartomatous lesions but also, from altered neuronal plasticity in the heterozygous tissue.Impaired Synaptic Plasticity in a Rat Model of Tuberous Sclerosisvon der Brelie C, Waltereit R, Zhang L, Beck H, Kirschstein TEur J Neurosci 2006;23:686–692 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, pairedpulse 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 γ-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.