Metabotropic glutamate receptor-dependent long-term depression is impaired due to elevated ERK signaling in the ?RG mouse model of tuberous sclerosis complex.

ABSTRACT: Tuberous sclerosis complex (TSC) and fragile X syndrome (FXS) are caused by mutations in negative regulators of translation. FXS model mice exhibit enhanced metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD). Therefore, we hypothesized that a mouse model of TSC, ?RG transgenic mice, also would exhibit enhanced mGluR-LTD. We measured the impact of TSC2-GAP mutations on the mTORC1 and ERK signaling pathways and protein synthesis-dependent hippocampal synaptic plasticity in ?RG transgenic mice. These mice express a dominant/negative TSC2 that binds to TSC1, but has a deletion and substitution mutation in its GAP-domain, resulting in inactivation of the complex. Consistent with previous studies of several other lines of TSC model mice, we observed elevated S6 phosphorylation in the brains of ?RG mice, suggesting upregulated translation. Surprisingly, mGluR-LTD was not enhanced, but rather was impaired in the ?RG transgenic mice, indicating that TSC and FXS have divergent synaptic plasticity phenotypes. Similar to patients with TSC, the ?RG transgenic mice exhibit elevated ERK signaling. Moreover, the mGluR-LTD impairment displayed by the ?RG transgenic mice was rescued with the MEK-ERK inhibitor U0126. Our results suggest that the mGluR-LTD impairment observed in ?RG mice involves aberrant TSC1/2-ERK signaling.

SUBMITTER: Chevere-Torres I 

PROVIDER: S-EPMC3276695 | biostudies-literature | 2012 Mar

REPOSITORIES: biostudies-literature