Posted November 13, 2015
Note: Bolded hyperlinks will direct you to the investigators' public and technical abstracts, and publications, if applicable.
Dr. Stuart Lipton (FY12; Scintillon Institute and University of California, San Diego) investigated whether Memantine (Namenda®, FDA-approved to treat dementia in Alzheimer's patients) and NitroMemantine (an improved derivative of Memantine with superior preclinical efficacy) may be used to treat neurological manifestations of individuals with TSC. He found that (1) Memantine treatment can restore synaptic plasticity and shows promise in ameliorating deficits in learning and memory, (2) NitroMemantine offered an additional benefit over Memantine in a neurobehavioral readout, and (3) treatment with Memantine mitigated, and NitroMemantine restored, the responses to fear conditioning in Tsc2+/- mice. These findings augment prior work showing that NitroMemantine can provide synaptic protection and rescue behavioral abnormalities more so than Memantine in Alzheimer's mouse models. Moreover, the new work provides preclinical evidence in an animal model that NitroMemantine may be beneficial for TSC patients.
Dr. Alan Dombkowski (FY13; Wayne State University) is studying how changes in 5-Hydroxymethylcytosine (5hmC) methylation of DNA contribute to dysregulation of epilepsy risk genes in epileptogenic cortical tubers in TSC. The outcomes of this research are expected to expand our understanding of the molecular contributors to epilepsy in TSC and generate new approaches to the treatment of epilepsy in TSC, as several drugs that inhibit 5hmC are currently in preclinical and clinical trials for other purposes.
Dr. Kimberly Raab-Graham (FY13; University of Texas, at Austin) is expanding her earlier studies on neuronal hyperexcitability as the basis for seizure activity. These studies have shown that mTOR activity represses the local synthesis of a voltage-gated potassium channel, Kv1.1, in dendrites. Dr. Raab-Graham will identify the unique properties of potassium channels regulated by mTOR activity versus those that are not. Additionally, she will test whether combined therapy of NMDAR antagonists and GABABR agonists will increase dendritic Kv1.1 channels, thereby reducing neuronal hyperexcitability/seizures.
Dr. James Goldman (FY14; Columbia University Medical Center) will determine how pathways downstream of mTORC1, as well as mTORC1-independent molecules, contribute to epileptogenesis and progression of epilepsy in TSC. Dr. Goldman will use systems biology/gene expression profiling, electrophysiological, biochemical, immunohistochemical, and behavioral studies to elucidate the causes of epileptic seizures in individuals with TSC.