NitroSynapsin for the treatment of neurological manifestations of tuberous sclerosis complex in a rodent model
| Autor: | Juan C. Piña-Crespo, Eliezer Masliah, Tomohiro Nakamura, Olga Prikhodko, Stuart A. Lipton, Chang-ki Oh, Shu-ichi Okamoto, Scott R. McKercher, Laurence M. Brill, Anthony Adame, Nobuki Nakanishi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Hippocampus Tuberous sclerosis Mice 0302 clinical medicine Tuberous Sclerosis Receptors Fear conditioning Mice Knockout Glutamate receptor Long-term potentiation medicine.anatomical_structure Mental Health Neurology Neurological NMDA receptor N-Methyl-D-Aspartate congenital hereditary and neonatal diseases and abnormalities Knockout Clinical Sciences Receptors N-Methyl-D-Aspartate Basic Behavioral and Social Science Article lcsh:RC321-571 03 medical and health sciences Glutamatergic Rare Diseases Tuberous Sclerosis Complex 2 Protein Behavioral and Social Science medicine Animals lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry Neurology & Neurosurgery business.industry Animal E/I imbalance Neurosciences medicine.disease nervous system diseases Brain Disorders Disease Models Animal 030104 developmental biology Hippocampal long-term potentiation NitroSynapsin Disease Models TSC1 TSC2 business Neuroscience Excitatory Amino Acid Antagonists 030217 neurology & neurosurgery Extrasynaptic NMDA receptor |
| Zdroj: | Neurobiol Dis Neurobiology of Disease, Vol 127, Iss, Pp 390-397 (2019) |
| Popis: | Tuberous sclerosis (TSC) is an autosomal dominant disorder caused by heterozygous mutations in the TSC1 or TSC2 gene. TSC is often associated with neurological, cognitive, and behavioral deficits. TSC patients also express co-morbidity with anxiety and mood disorders. The mechanism of pathogenesis in TSC is not entirely clear, but TSC-related neurological symptoms are accompanied by excessive glutamatergic activity and altered synaptic spine structures. To address whether extrasynaptic (e)NMDA-type glutamate receptor (NMDAR) antagonists, as opposed to antagonists that block physiological phasic synaptic activity, can ameliorate the synaptic and behavioral features of this disease, we utilized the Tsc2+/− mouse model of TSC to measure biochemical, electrophysiological, histological, and behavioral parameters in the mice. We found that antagonists that preferentially block tonic activity as found at eNMDARs, particularly the newer drug NitroSynapsin, provide biological and statistically significant improvement in Tsc2+/− phenotypes. Accompanying this improvement was correction of activity in the p38 MAPK-TSC-Rheb-mTORC1-S6K1 pathway. Deficits in hippocampal long-term potentiation (LTP), histological loss of synapses, and behavioral fear conditioning in Tsc2+/− mice were all improved after treatment with NitroSynapsin. Taken together, these results suggest that amelioration of excessive excitation, by limiting aberrant eNMDAR activity, may represent a novel treatment approach for TSC. |
| Databáze: | OpenAIRE |
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