Learning and memory requires multiple forms of synaptic plasticity mediated by mGlu, NMDA, AMPA glutamate receptors (mGluR, NMDAR, AMPAR). These plasticity mechanisms include long-term potentiation (LTP) and depression (LTD), that rapidly increase or decrease synaptic strength of specific inputs, and homeostatic synaptic scaling, which scale-up or -down strength of all inputs. Importantly, alterations in LTP/LTD and homeostatic plasticity are associated with cognitive dysfunction in animal models of nervous system disorders. Until recently, the signaling mechanisms controlling AMPARs during LTP/LTD and homeostatic plasticity were envisioned as distinct. However, LTP/LTD and homeostatic plasticity can both result in synaptic incorporation of high-conductance, Ca2+-permeable AMPA receptors (CP-AMPAR) containing GluA1, but lacking GluA2, subunits that not only impact synaptic strength but also alter plasticity itself - i.e. metaplasticity. Nevertheless, the roles of CP-AMPARs in controlling plasticity in hippocampal neurons are controversial. A major barrier to moving the field forward has been that we do not have an adequate understanding of the signaling mechanisms that control CP-AMPARs. Importantly, recent studies from our laboratory employing knock-in mice demonstrated that the kinase PKA and phosphatase Calcineurin (CaN) anchored to A-kinase anchoring protein (AKAP) 79/150 play opposing roles regulating GluA1 phosphorylation to control both basal and plasticity-regulated CP-AMPAR synaptic incorporation at hippocampal synapses. In particular, we found that AKAP-PKA/CaN positive/negative regulation of CP-AMPAR synaptic incorporation controls LTP/LTD balance and determines whether synapses can undergo homeostatic potentiation. In addition, we found that palmitoylation/depalmitoylation of the AKAP N-terminal targeting domain controls AKAP delivery/removal from dendritic spines in coordination with cellular correlates of LTP/LTD. Furthermore, recent unpublished work indicates that knock-in disruption of AKAP palmitoylation in vivo increases basal CP-AMPAR activity to prevent subsequent LTP. Finally, both published and unpublished data indicate that these CP- AMPAR-mediated changes in plasticity are influenced by developmental age, induction stimulus, and crosstalk with CaMKII and mGlu1 signaling suggesting engagement of metaplasticity. Here we will use the unique knock-in mice we developed to test the overall hypothesis that regulation of AKAP postsynaptic targeting by palmitoylation (aim 1) and CaMKII signaling (aim 2), and interactions between AKAP-PKA/CaN and mGluR signaling (aim 3) control LTP/LTD balance at CA1 synapses through CP-AMPAR-mediated metaplasticity.
This project is focused on understanding the basic fundamental mechanisms that control the function of synaptic connections between neurons in the brain. Modulation of the strength of synaptic connections, known as synaptic plasticity, is thought to be central to normal processes of learning and memory. In addition, abnormal plasticity is associated with many brain disorders that are characterized by altered cognitive function and behavior, including Alzheimer's disease, epilepsy, schizophrenia, autism, Fragile-X syndrome, Rett syndrome, stroke, epilepsy, and traumatic brain injury. Thus, it is important to understand molecular mechanisms of synaptic plasticity and how these mechanisms are controlled both under normal and disease conditions. Here we will study how a protein molecule called AKAP79/150 (79 in humans/ 150 in mice) that organizes other important synaptic regulatory proteins called protein kinases and phospatases is targeted to different locations in and near synapses through addition of a fat molecule called palmitate. This process of adding palmitate to proteins is called palmitoylation, and altered palmitoylation regulation has also been linked to multiple brain disorders, including epilepsy, Huntington's disease, schizophrenia, and X-linked mental retardation. Importantly, the research we propose here seeks to understand how altering palmitolyation of AKAP79/150 impacts its targeting in and near synapses, and thus, also its ability to control synaptic plasticityin mice. In particular, we are interested in how this AKAP79/150 molecule and its associated kinases and phosphatases control and interact with specific types of synaptic receptor molecules called Calcium-permeable AMPA receptors and metabotropic glutamate receptors, which play key roles regulating synaptic plasticity in normal learning and memory but also altered synaptic plasticity following drug addiction, stroke, and seizures. Thus, by determining how these fundamental synaptic regulatory mechanisms work we will add to our basic science knowledge base of neuronal processes that underlie normal nervous system function, and also hopefully aid in understanding how these processes may be altered by diseases leading to nervous system dysfunction.
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