Integration of long-term-memory-related synaptic plasticity involves bidirectional regulation of gene expression and chromatin structure

Excitatory and inhibitory inputs converge on single neurons and are integrated into a coherent output. Although much is known about short-term integration, little is known about how neurons sum opposing signals for long-term synaptic plasticity and memory storage. In Aplysia, we find that when a sensory neuron simultaneously receives inputs from the facilitatory transmitter 5-HT at one set of synapses and the inhibitory transmitter FMRFamide at another, long-term facilitation is blocked and synapse-specific long-term depression dominates. Chromatin immunoprecipitation assays show that 5-HT induces the downstream gene C/EBP by activating CREB1, which recruits CBP for histone acetylation, whereas FMRFa leads to CREB1 displacement by CREB2 and recruitment of HDAC5 to deacetylate histones. When the two transmitters are applied together, facilitation is blocked because CREB2 and HDAC5 displace CREB1-CBP, thereby deacetylating histones.     

Ubiquitin-proteasome-mediated CREB repressor degradation during induction of long-term facilitation

Abstract Long-term facilitation in Aplysia and other forms of long-term memory in invertebrates and vertebrates require the gene expression cascade induced by cAMP-responsive element binding protein (CREB). Normally, gene expression by CREB is inhibited by repressors. The molecular mechanisms by which the repression is relieved are not understood. Our results show that Aplysia CREB repressor is a substrate for degradation by the ubiquitin-proteasome pathway. Treatment with the facilitatory neurotransmitter 5-hydroxy tryptamine (5-HT) leads to CREB repressor degradation in vivo and the degradation can be blocked by a specific proteasome inhibitor. Our biochemical studies show that attachment of ubiquitin molecules marks the CREB repressor for degradation by the proteasome. Protein kinase C (PKC) stimulates ubiquitination and degradation of the CREB repressor. Our results suggest that proteolytic removal of the CREB repressor is a potential mechanism for controlling gene expression by CREB. Without stimulation, gene expression is suppressed by the CREB repressor. Upon stimulation with 5-HT, PKC is activated, causing enhancement in ubiquitination and degradation of the CREB repressor. Thus, regulation of proteolysis of the CREB repressor by PKC might be critical in determining whether or not CREB-mediated gene expression goes forward during induction of long-term facilitation.