Dysregulated Expression Of Neuregulin-1 By Cortical Pyramidal Neurons Disrupts Synaptic Plasticity

Neuregulin-1 (NRG1) gene variants are associated with increased genetic risk for schizophrenia. It is unclear whether risk haplotypes cause elevated ordecreased expression of NRG1 in the brains of schizophrenia patients, given that both findings have been reported from autopsy studies. To study NRG1 functions invivo, we generated mouse mutants with reduced and elevated NRG1 levels and analyzed the impact on cortical functions. Loss of NRG1 from cortical projection neurons resulted in increased inhibitory neurotransmission, reduced synaptic plasticity, and hypoactivity. Neuronal overexpression of cysteine-rich domain (CRD)-NRG1, the major brain isoform, caused unbalanced excitatory-inhibitory neurotransmission, reduced synaptic plasticity, abnormal spine growth, altered steady-state levels of synaptic plasticity-related proteins, and impaired sensorimotor gating. We conclude that an "optimal" level of NRG1 signaling balances excitatory and inhibitory neurotransmission in the cortex. 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Discovery and Structure Activity Relationships of N Aryl 6 Aminoquinoxalines as Potent PFKFB3 Kinase Inhibitors

Energy and biomass production in cancer cells are largely supported by aerobic glycolysis in what is called the Warburg effect. The process is regulated by key enzymes, among which phosphofructokinase PFK 2 plays a significant role by producing fructose 2,6 biphosphate; the most potent activator of the glycolysis rate limiting step performed by phosphofructokinase PFK 1. Herein, the synthesis, biological evaluation and structure activity relationship of novel inhibitors of 6 phosphofructo 2 kinase fructose 2,6 biphosphatase amp; 8197;3 PFKFB3 , which is the ubiquitous and hypoxia induced isoform of PFK 2, are reported. X ray crystallography and docking were instrumental in the design and optimisation of a series of N aryl 6 aminoquinoxalines. The most potent representative, N 4 methanesulfonylpyridin 3 yl 8 3 methyl 1 benzothiophen 5 yl quinoxalin 6 amine, displayed an IC50 of 14 amp; 8197;nm for the target and an IC50 of 0.49 amp; 8197; amp; 956;m for fructose 2,6 biphosphate production in human colon carcinoma HCT116 cells. This work provides a new entry in the field of PFKFB3 inhibitors with potential for development in oncolog