Long-term activity-induced changes in the brain : a study of translational regulation and structural plasticity

Abstract

Long-lasting changes must take place in the brain to store the skills and memories that have been learned by the organism throughout its history. Long-term memory (LTM), and its cellular correlate, the late-phase of long-term potentiation (L-LTP), require protein synthesis. It has generally been assumed that the regulation of transcription underlies L-LTM and LTM. Chapter 2 of this thesis demonstrates that transgenic mice with inhibited ERK MAP Kinase pathway activity in the cortex and CA1 region of the hippocampus show inhibited LTM and L-LTP. Moreover, the L-LTP phenotype resembles a deficit in translation and not transcription. Experiments using hippocampal cultured cells demonstrate that neuronal activity induces translation of a large number of mRNAs in an ERK MAP Kinase pathway-dependent manner via phosphorylation of the translation factors S6, elF4E and 4E-BP1. Increased phosphorylation of translation factors was observed along with increased translation after the induction of L-LTP; lastly, LTM formation occurred concomitantly with ERK MAP Kinase pathway-dependent phosphorylation of S6 and elF4E. Chapter 3 extends these findings to demonstrate that other stimuli that cause protein synthesis-dependent forms of plasticity also upregulate protein synthesis via the same mechanisms.

(cont.) As some of these stimuli cause L-LTP and others cause L-LTD, it is proposed that induction of these forms of plasticity, though opposite in terms of synaptic-weight changes, produce the same proteins, and that activated synapses capture the appropriate proteins to express the appropriate form of synaptic plasticity. Cellularly, it is believed that these long-lasting changes involve structural plasticity in the neurons. However, as it has generally been difficult to show such a correlation between structural changes and behavioral changes after behavioral training, a correlation between structural changes and affective behaviors after chronic-stress treatment was sought. Chapter 4 shows that transgenic mice overexpressing BDNF only in forebrain pyramidal cells have reduced chronic stress-induced atrophy in the apical dendrites of CA3 pyramidal cells. This structural change is correlated with improved performance in the Porsolt forced-swim test. Increased spinogenesis was observed in the amygdala concomitantly with an increase in anxiety, thus demonstrating a strong correlation between structural change and behavior.