The roles of calpains and SIRT1 in rodent hippocampal synaptic plasticity.

摘要

Learning and memory are important functions shared by the living world. In humans, these two functions are a result of brain plasticity and have been studied extensively in the hippocampus, a forebrain structure residing in the medial temporal lobe. Hippocampus is best known for participating in the formation of episodic memory and for exhibiting a special form of synaptic plasticity---long-term potentiation (LTP). LTP is a long lasting enhancement of synaptic transmission resulting from high frequency stimulation of presynaptic neurons. LTP is widely accepted as a molecular biological mechanism underlying certain types of learning and memory. In this dissertation, I evaluate the roles of two protein families, calpain and sirtuin, in rodent hippocampal LTP and contextual fear conditioning learning, which is a hippocampus-dependent task. Calpain is a calcium-dependent neutral protease and sirtuin is NAD +-dependent deacetylase. By using calpastatin (an endogenous calpain inhibitor) knockout and over-expressing mice, as well as viral vector-mediated in vivo shRNA interference targeting two ubiquitous calpain isoforms (mu- and m- calpains) in adult rats, I found that calpains might not be directly implicated in the type of LTP induced by customized theta burst stimuli. On the other hand, different calpain isoform deficiencies led to changes in cell excitability, presynaptic properties and NMDA receptor-mediated synaptic responses. In contrast, SIRT1 (sirtuin-1) knockout mice revealed the indispensable requirement of SIRT1 for normal learning, memory and LTP, while over-expressing SIRT1 in the brain did not substantially affect learning and memory or synaptic plasticity.