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.

Reconstruction and regeneration of the central nervous system (CNS) following injury is a formidable task. However, cell replacement with transplanted neural progenitor cells (NPC) is a promising technique that has resulted in various levels of functional recovery in animals that had experienced an experimental injury of the brain or spinal cord. Unfortunately, CNS injury often leads to significant tissue damage and loss, limiting the survival and integration of transplanted NPC. In response, researchers have developed many biomaterial substrates that have been used to culture, transplant, and influence the differentiation and integration of transplanted NPC. Biomaterial scaffolds are a three-dimensional lattice that can be engineered to support NPC in vitro as well as serving as a temporary extracellular matrix (ECM) after transplantation. Scaffold modification with bioactive components, such as proteins, adhesive peptide sequences, and growth factors, allow researchers to modulate NPC responses as well as the local environment of the transplantation site. Biomimetic approaches also can include materials that recapitulate the structural dimensions of the ECM, namely self-assembling nanofibers. These materials can be useful for altering the tissue microenvironment by reducing inflammation and glial scarring, which may further enhance NPC survival and integration into functional neural circuitry. This review describes various biomaterial constructs, with a focus on biomimetic systems that have been used in modulating NPC behavior in culture and/or in transplanting NPC to the CNS.

A mouse model of the human genetic disorder tuberous sclerosis complex fails to undergo developmental down-regulation of mGluR5 expression and activation of Erk signaling, probably contributing to the aberrant plasticity and epilepsy in this disease.

The 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 demonstrate that loss of REST results in up-regulation 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 demonstrate a critical role for the REST-LIN28A axis in tumor aggression and suggest a causative relationship between REST loss and tumorigenicity in vivo.

NEURO-ONCOLOGY • NOVEMBER 2017 diagnosed glioblastomas (GBM). However, the optimal cycles of adjuvant TMZ remains controversial. Until December 2013 we treated patients with GBM with maximum 24 cycles of adjuvant TMZ (24C group, N=122), and after January 2014 changed our treatment policy to maximum 12 cycles (12C group, N=26). The aim of this study was to explore an impact of extended TMZ treatment on outcome with comparison between 12C group and 24C group. METHODS: Between May 2006 and March 2016 we included 148 patients with newly diagnosed GBM whose number of cycles of adjuvant TMZ was available. In 119 patients, IDH1/2 mutations and MGMT promoter methylation status were analyzed by direct sequencing and pyrosequencing, respectively. Methylation was defined as positive when the mean level of methylation at the 16 CpG sites examined was greater than 16%. RESULTS: The median survival time (MST) and progression free survival (mPFS) were 18.1 months and 9.9 months, respectively. The median number of adjuvant TMZ cycles was 6, and 31 patients (20.9%) received 13 cycles or more. The MST and mPFS did not differ significantly between 12C group and 24C group (30.3 vs 18.1 months, p=0.26, 12.3 vs 9.6 months, p=0.23, respectively). The time from the end of 12 cycles to progression did not differ between patients who completed 12 cycles and stop and those who continued more than 12 cycles (progression free survival rate at 6 months: 62.5% vs 66.7%, p=0.65). Multivariate analysis indicated that age, extent of resection, postoperative Karnofsky performance status, and MGMT promoter methylation were associated with prolonged survival time, but not the number of adjuvant TMZ cycles (p=0.28). CONCLUSIONS: Extended TMZ beyond 12 cycles did not prevent tumor recurrence and was not associated with improved outcome.