UCSF

The most striking feature of the brain is its seemingly endless ability to learn, to adapt to new experiences, and to remember. All of this information is encoded in the connections, or synapses, between neurons. These synapses change during learning and new memory formation in a process called synaptic plasticity. While much has been learned about the molecular mechanisms involved in synaptic plasticity, there is a long way to go before these processes are fully understood. In order to better understand these long-term changes, we focus on the roles of the novel kinase PKD1 (PKD1) and the scaffolding protein yotiao, a member of the A-kinase anchoring protein (AKAP) superfamily. In particular, we look at the roles of these proteins in the intracellular signaling pathways that originate with the NMDA-type glutamate receptor (NMDAR), a well-characterized and important glutamate receptor that plays a critical role in many forms of synaptic plasticity. We show that PKD1 is a downstream target of NMDA receptor signaling and participates in synaptic plasticity by regulating the trafficking of AMPA-type glutamate receptors (AMPARs). Since changes in gene expression are critical for the long-term maintenance of synaptic plasticity, we also look at signaling to the nucleus. In response to certain stimuli, we find that PKD1 is capable of controlling the function of HDACs, a family of transcriptional repressors that regulate gene expression. Finally, we find that yotiao, which binds to NMDARs in a splice variant-dependent way, may play a role in facilitating signaling from the NMDAR to CREB, a transcription factor important to synaptic plasticity. By better understanding the functions of PKD1 and yotiao in neurons, we gain new insights into the molecular mechanisms of synaptic change, and thus, learning and memory.