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J Neurosci. 2011 Jun 15;31(24):8862-9. doi: 10.1523/JNEUROSCI.1617-11.2011.

Loss of Tsc1 in vivo impairs hippocampal mGluR-LTD and increases excitatory synaptic function.

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  • 1Howard Hughes Medical Institute, Department of Neurobiology, Harvard Medical School, Boston, Massachusetts 02115, USA.

Abstract

The autism spectrum disorder tuberous sclerosis complex (TSC) is caused by mutations in the Tsc1 or Tsc2 genes, whose protein products form a heterodimeric complex that negatively regulates mammalian target of rapamycin-dependent protein translation. Although several forms of synaptic plasticity, including metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), depend on protein translation at the time of induction, it is unknown whether these forms of plasticity require signaling through the Tsc1/2 complex. To examine this possibility, we postnatally deleted Tsc1 in vivo in a subset of hippocampal CA1 neurons using viral delivery of Cre recombinase in mice. We found that hippocampal mGluR-LTD was abolished by loss of Tsc1, whereas a protein synthesis-independent form of NMDA receptor-dependent LTD was preserved. Additionally, AMPA and NMDA receptor-mediated EPSCs and miniature spontaneous EPSC frequency were enhanced in Tsc1 KO neurons. These changes in synaptic function occurred in the absence of alterations in spine density, morphology, or presynaptic release probability. Our findings indicate that signaling through Tsc1/2 is required for the expression of specific forms of hippocampal synaptic plasticity as well as the maintenance of normal excitatory synaptic strength. Furthermore, these data suggest that perturbations of synaptic signaling may contribute to the pathogenesis of TSC.

PMID:
21677170
[PubMed - indexed for MEDLINE]
PMCID:
PMC3133739
Free PMC Article
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