抑制Phosphodiesterase-4B 與 強化記憶 潛力 !!

改變老鼠基因不怕貓　有助抗癡呆症 2015年08月15日18:41 醫學界對抗癡呆症的研究再有突破，英國及加拿大科學家透過改變老鼠基因，使老鼠變得更加聰明及減少焦慮，日後有望研製出新藥對抗阿茲海默氏症 （Alzheimer's）、精神分裂（schizophrenia）及創傷後壓力症（Post-traumatic stress disorder）等腦疾。英國《每日郵報》報導，研究員在實驗中，改動了老鼠的一組基因，藉此封鎖在腦部及不同器官都常見的「磷酸二酯酶4B」（PDE4B） 基因，結果牠們比普通老鼠學習速度更快，記憶力更強，而且更擅於解決複雜的問題，包括能對見過的同類有更深記憶、更快地學會找迷宮出口，同時減少了焦慮，與一般老鼠不同，牠們喜歡留在光亮的地方，也降低了對貓尿的恐懼。這項實驗證明了「磷酸二酯酶4B」對老鼠的學習及記憶有重要影響。研究員下一步是開發出抑壓「磷酸二酯酶4B」的藥物，並進行動物實驗，再判斷能否用作為人類診治阿茲海默氏症等腦疾。研究在《神經精神藥理學》期刊（Neuropsychopharmacology）發表。

Specific Inhibition of Phosphodiesterase-4B Results in Anxiolysis and Facilitates Memory Acquisition  Neuropsychopharmacology accepted article preview 14 August 2015; Cognitive dysfunction is a core feature of dementia and a prominent feature in psychiatric disease. As non-redundant regulators of intracellular cAMP gradients, phosphodiesterases (PDE) mediate fundamental aspects of brain function relevant to learning, memory, and higher cognitive functions. Phosphodiesterase-4B (PDE4B) is an important phosphodiesterase in the hippocampal formation, is a major Disrupted in Schizophrenia 1 (DISC1) binding partner and is itself a risk gene for psychiatric illness. To define the effects of specific inhibition of the PDE4B subtype, we generated mice with a catalytic domain mutant form of PDE4B (Y358C) that has decreased ability to hydrolyze cAMP. Structural modelling predictions of decreased function and impaired binding with DISC1 were confirmed in cell assays. Phenotypic characterization of the PDE4BY358C mice revealed facilitated phosphorylation of CREB, decreased binding to DISC1, and upregulation of DISC1 and β-Arrestin in hippocampus and amygdala. In behavioural assays, PDE4BY358C mice displayed decreased anxiety and increased exploration, as well as cognitive enhancement across several tests of learning and memory, consistent with synaptic changes including enhanced long-term potentiation and impaired depotentiation ex vivo. PDE4BY358C mice also demonstrated enhanced neurogenesis. Contextual fear memory, though intact at 24 h, was decreased at 7 days in PDE4BY358C mice, an effect replicated pharmacologically with a non-selective PDE4 inhibitor, implicating cAMP signalling by PDE4B in a very late phase of consolidation. No effect of the PDE4BY358C mutation was observed in the pre-pulse inhibition and forced swim tests. Our data establish specific inhibition of PDE4B as a promising therapeutic approach for disorders of cognition and anxiety, and a putative target for pathological fear memory.