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

Abstract

The autismspectrum disordertuberous sclerosis complex (TSC)iscausedbymutationsintheTsc1orTsc2genes, whoseprotein 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), de-pendonprotein translationatthe timeof induction,itis unknown whether these formsof 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 Tsc1KO neurons. These changes in synaptic function occurred inthe absence of alterations in spine density, morphology, or presynaptic release probability. Our findings indicate that signaling through Tsc1/2 is required for the expression ofspecific formsof hippocampal synaptic plasticityas wellas the maintenance of normal excitatory synaptic strength. Furthermore, these data suggest that perturbations of synaptic signaling may contribute to the pathogenesis of TSC. © 011 the authors.