UCLA

Synaptic plasticity, changes in the number and strength of synaptic connections in the brain, represents the best-characterized correlate of learning and memory. Long-term synaptic plasticity is a transcription- and translation-dependent process that can be restricted to subsets of synapses within a single neuron. The model system Aplysia californica provides an excellent model system to study the cellular and molecular mechanisms underlying long-term, learning- related synaptic plasticity. In this thesis, I investigate two cell biological questions that emerge from the requirement for gene expression during synapse-specific plasticity. The first question concerns the spatial regulation of gene expression within neurons. Here, we propose that one mechanism for restricting gene expression to individual synapses is through mRNA localization and regulated translation. I have identified a 66 nucleotide sequence in the 5'UTR of sensorin mRNA that when paired with the sensorin 3'UTR is required and sufficient for sensorin mRNA synaptic localization. My experiments further indicate that this localization element is encoded by a stem-loop structure (Meer et al., 2012). The second question concerns the mechanisms by which synaptically-generated signals are transported from the synapse to the nucleus to initiate transcription. Using the Aplysia sensory-motor co-culture system, I found that the transcriptional regulator CREB-regulated transcriptional co-activator (CRTC) is required for activity-dependent long-term facilitation. Aplysia CRTC (ApCRTC) accumulates in the nucleus when cultures are treated with stimulation inducing activity-dependent heterosynaptic plasticity, but not when treated with activity-independent heterosynaptic plasticity inducing stimulation. Electrophysiological studies show that ApCRTC is functionally required in the postsynaptic (motor) neuron, as injection of dominant-negative constructs block long-term synaptic plasticity.