Enhanced episodic‐like memory and kindling epilepsy in a rat model of tuberous sclerosis

Abstract

Tuberous 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.

Spatial Memory Formation and Memory-Enhancing Effect of Glucose Involves Activation of the Tuberous Sclerosis Complex–Mammalian Target of Rapamycin Pathway

“…As hypothesized previously, synapse-specific protein synthesis is thought to serve as a tag for the maintenance of long-term plasticity (Frey and Morris, 1997;Martin et al, 1997b). A recent study reports that Eker rats, heterozygous for tsc2 (tsc ϩ/ Ϫ , which would cause modest activation of the mTOR cascade) show enhanced episodic-like memory (Waltereit et al, 2006). The present study supports these previous findings and additionally implicates the TSC-mTOR pathway in hippocampal-dependent long-term memory storage.…”

Epilepsy and Tsc2 Haploinsufficiency Lead to Autistic-Like Social Deficit Behaviors in Rats

“…None of the models exhibit spontaneous seizure activity. Although there is substantial variation between the different animals, all models express changes in learning and memory with the Tsc1 ?/-mice showing deficits in social behavior as well (Waltereit et al 2006;Goorden et al 2007;Ehninger et al 2008). Taking together the current human and animal data, results suggest that seizures may not be necessary to cause ASD (de Vries and Howe 2007;Goorden et al 2007), and that there might be direct genetic effects (Smalley 1998;de Vries and Howe 2007).…”

“…Illumination was 30 lux. Animals were trained for 5 days three times a day with 2 h intervals (Waltereit et al 2006). After a total of 15 training trials, the probe trial was performed with the platform removed (probe trial duration = 60 s).…”

mTOR inhibitor reverses autistic-like social deficit behaviours in adult rats with both Tsc2 haploinsufficiency and developmental status epilepticus

“…This social deficit in adult rats was accelerated by the previous experience of DSE induced during early childhood in these Tsc2 +/− (Eker)-rats [16][17][18]. Given that patients with ASD in TSC often have a history of previous developmental epilepsy, the P7 and P14 DSE scenario in Tsc2 +/− (Eker)-rats suggests an animal model of impaired social behaviour, closer to the situation of TSC patients than those caused by a Tsc1 or Tsc2 mutation alone.…”