Cognitive deficits in Tsc1+/- mice in the absence of cerebral lesions and seizures.
OBJECTIVE
Tuberous sclerosis complex (TSC) is characterized by brain lesions, epilepsy, increased incidence of mental retardation and autism. The causal link between lesion load and epilepsy on cognitive disabilities has been debated, and these factors explain only part of the intelligence quotient variability. A Tsc2 rat model of the disease provided evidence that the TSC genes are directly involved in neuronal function. However, these lesion- and epilepsy-free animals did not show learning deficits, leaving open the possibility that the presence of brain lesions or epilepsy is a prerequisite for the cognitive deficits to fully develop. Here, we reinvestigated the relation among cerebral lesions, epilepsy, and cognitive function using Tsc1+/- mice.


METHODS
We used immunocytochemistry and high-resolution magnetic resonance imaging to study the presence of neuronal pathology in Tsc1+/- mice. We used the Morris water maze, fear conditioning, social interaction, and nest building test to study the presence of cognitive and social deficits.


RESULTS
We observed no spontaneous seizures or cerebral lesions in the brains of Tsc1+/- mice. In addition, giant dysmorphic cells were absent, and spine number and dendritic branching appeared to be normal. Nevertheless, Tsc1+/- mice showed impaired learning in the hippocampus-sensitive versions of the learning tasks and impaired social behavior.


CONCLUSIONS
Tsc1+/- mice show social and cognitive deficits in the absence of apparent cerebral pathology and spontaneous seizures. These findings support a model in which haploinsufficiency for the TSC genes leads to aberrations in neuronal functioning resulting in impaired learning and social behavior.
Goorden
Susanna M I
SM
Department of Neuroscience, Erasmus MC University Medical Center, Rotterdam, The Netherlands.
van Woerden
Geeske M
GM
van der Weerd
Louise
L
Cheadle
Jeremy P
JP
Elgersma
Ype
Y
D000818:Animals; D001522:Behavior, Animal; D001921:Brain / Q000473:pathology*; D003072:Cognition Disorders / Q000235:genetics* / Q000473:pathology* / Q000523:psychology; D003213:Conditioning, Psychological; D003712:Dendrites / Q000473:pathology; D005239:Fear; D018782:Maze Learning; D051379:Mice; D009154:Mutation; D009425:Nesting Behavior; D012640:Seizures / Q000235:genetics*; D012919:Social Behavior; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins / Q000235:genetics*
C000624651:Tsc1 protein, mouse; C000624652:Tsc1 protein, rat; D000077004:Tuberous Sclerosis Complex 1 Protein; D025521:Tumor Suppressor Proteins