Reduced juvenile long-term depression in tuberous sclerosis complex is mitigated in adults by compensatory recruitment of mGluR5 and Erk signaling.

Tuberous sclerosis complex (TSC) is a multisystem genetic disease that manifests with mental retardation, tumor formation, autism, and epilepsy. Heightened signaling through the mammalian target of rapamycin (mTOR) pathway is involved in TSC pathology, however it remains unclear how other signaling pathways are perturbed and contribute to disease symptoms. Reduced long-term depression (LTD) was recently reported in TSC mutant mice. We find that although reduced LTD is a feature of the juvenile mutant hippocampus, heightened expression of metabotropic glutamate receptor 5 and constitutively activated Erk signaling in the adult hippocampus drives wild-type levels of LTD. Increased mGluR5 and Erk results in a novel mTOR-independent LTD in CA1 hippocampus of adult mice, and contributes to the development of epileptiform bursting activity in the TSC2(+/-) CA3 region of the hippocampus. Inhibition of mGluR5 or Erk signaling restores appropriate mTOR-dependence to LTD, and significantly reduces epileptiform bursting in TSC2(+/-) hippocampal slices. We also report that adult TSC2(+/-) mice exhibit a subtle perseverative behavioral phenotype that is eliminated by mGluR5 antagonism. These findings highlight the potential of modulating the mGluR5-Erk pathway in a developmental stage-specific manner to treat TSC.

Induction of the RNA regulator LIN28A is required for the growth and pathogenesis of RESTless breast tumors.

The transcription factor RE1 silencing transcription factor (REST) is lost in approximately 20% of breast cancers. Although it is known that these RESTless tumors are highly aggressive and include all tumor subtypes, the underlying tumorigenic mechanisms remain unknown. In this study, we show that loss of REST results in upregulation of LIN28A, a known promoter of tumor development, in breast cancer cell lines and human breast tumors. We found that LIN28A was a direct transcriptional target of REST in cancer cells and that loss of REST resulted in increased LIN28A expression and enhanced tumor growth both in vitro and in vivo, effects that were dependent on heightened LIN28A expression. Tumors lacking REST expression were locally invasive, consistent with the increased lymph node involvement observed in human RESTless tumors. Clinically, human RESTless breast tumors also displayed significantly enhanced LIN28A expression when compared with non-RESTless tumors. Our findings therefore show a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo.

Metabolic regulation of neuronal plasticity by the energy sensor AMPK.

Long Term Potentiation (LTP) is a leading candidate mechanism for learning and memory and is also thought to play a role in the progression of seizures to intractable epilepsy. Maintenance of LTP requires RNA transcription, protein translation and signaling through the mammalian Target of Rapamycin (mTOR) pathway. In peripheral tissue, the energy sensor AMP-activated Protein Kinase (AMPK) negatively regulates the mTOR cascade upon glycolytic inhibition and cellular energy stress. We recently demonstrated that the glycolytic inhibitor 2-deoxy-D-glucose (2DG) alters plasticity to retard epileptogenesis in the kindling model of epilepsy. Reduced kindling progression was associated with increased recruitment of the nuclear metabolic sensor CtBP to NRSF at the BDNF promoter. Given that energy metabolism controls mTOR through AMPK in peripheral tissue and the role of mTOR in LTP in neurons, we asked whether energy metabolism and AMPK control LTP. Using a combination of biochemical approaches and field-recordings in mouse hippocampal slices, we show that the master regulator of energy homeostasis, AMPK couples energy metabolism to LTP expression. Administration of the glycolytic inhibitor 2-deoxy-D-glucose (2DG) or the mitochondrial toxin and anti-Type II Diabetes drug, metformin, or AMP mimetic AICAR results in activation of AMPK, repression of the mTOR pathway and prevents maintenance of Late-Phase LTP (L-LTP). Inhibition of AMPK by either compound-C or the ATP mimetic ara-A rescues the suppression of L-LTP by energy stress. We also show that enhanced LTP via AMPK inhibition requires mTOR signaling. These results directly link energy metabolism to plasticity in the mammalian brain and demonstrate that AMPK is a modulator of LTP. Our work opens up the possibility of using modulators of energy metabolism to control neuronal plasticity in diseases and conditions of aberrant plasticity such as epilepsy.