Synaptic plasticity, the activity dependent change in the strength of neuronal connections, is thought to underlie memory storage and may play an important role in several neurological and psychiatric disorders including epilepsy, Alzheimer's disease and mental retardation. Studies of the molecular biology of learning and memory have identified several crucial signaling cascades involved in synaptic plasticity in mice, flies and Aplysia. Of particular interest to our laboratory is the cAMP dependent protein kinase (PKA) signaling pathway and its role in hippocampal long-term potentiation (LTP). LTP in the mammalian hippocampus is a well studied form of synaptic plasticity. Our work has demonstrated that PKA is critically important for a long-lasting form of LTP (L-LTP) at Schaffer collateral-CA1 synapses (Abel et al., 1997; Woo et al., 2000). PKA holoenyzme is typically restricted to discrete subcellular regions through interactions between the regulatory subunits and A-kinase anchoring proteins (AKAPs). Recent work has shown that transgenic animals that inducibly express Ht-31 (a peptide inhibitor of AKAP/PKA interaction) display altered hippocampus-dependent learning and memory phenotypes, demonstrating the importance of PKA anchoring in hippocampal function. This proposal seeks to extend these studies using genetically modified mice, immunohistochemical, imaging and electrophysiological techniques to elucidate the role of AKAPs in regulating the function of PKA in synaptic plasticity within the hippocampus.
| Isiegas, Carolina; McDonough, Conor; Huang, Ted et al. (2008) A novel conditional genetic system reveals that increasing neuronal cAMP enhances memory and retrieval. J Neurosci 28:6220-30 |
| Vecsey, Christopher G; Hawk, Joshua D; Lattal, K Matthew et al. (2007) Histone deacetylase inhibitors enhance memory and synaptic plasticity via CREB:CBP-dependent transcriptional activation. J Neurosci 27:6128-40 |
| Huang, Ted; McDonough, Conor B; Abel, Ted (2006) Compartmentalized PKA signaling events are required for synaptic tagging and capture during hippocampal late-phase long-term potentiation. Eur J Cell Biol 85:635-42 |
