Neurons in the mammalian central nervous system communicate with each other via synapses. The dendrites of cells which receive excitatory glutamatergic input are highly complex structures, and covered in tiny membranous protuberances called dendritic spines. Spines house the postsynaptic density and associated machinery that constitute the post-synaptic side of the synapse, and while significant progress has been made in understanding the interactions and physiology of these proteins, many questions remain. Recent advances in optical techniques have allowed for stimulating individual synapses and simultaneously visualizing local neuronal activity on the fine spatial scale of single dendritic spines. We propose to use these methods to investigate the interplay of postsynaptic ion channels at individual synapses. The specific goal of this work is to obtain a detailed understanding of the events that shape the postsynaptic responses at single synapses on the dendrites of CA1 pyramidal neurons. In particular, the experiments proposed here will address two main questions. First, what are the signaling events downstream of glutamate receptor activation that shape potentials and calcium ion accumulation in dendritic spines? Secondly, are calcium signals in spines of CA1 pyramidal neurons influenced by near-coincident synaptic activity and action potentials? To address these questions, we will use a combination of whole-cell patch clamp physiology, 2-photon scanning laser microscopy (2PLSM), and 2-photon laser uncaging of glutamate to stimulate and record events in individual dendritic spines. More generally, this proposal aims to explore fundamental aspects of the events that underlie communication between neurons. Changes in the strength of connections between neurons in the central nervous system are thought to underlie learning and memory, and understanding the complex signaling events that occur in dendritic spines is crucial to understanding these phenomena. Furthermore, many mutations in proteins located in spines are linked to human neurological disorders, and spine morphology is perturbed in many mouse models of neurological diseases. Understanding the properties of synaptic transmission and the signaling dynamics in spines is vital to explaining the cellular mechanisms of neurodegenerative disorders like Alzheimer's and Parkinson's diseases.
| Carter, Brett C; Giessel, Andrew J; Sabatini, Bernardo L et al. (2012) Transient sodium current at subthreshold voltages: activation by EPSP waveforms. Neuron 75:1081-93 |
| Giessel, Andrew J; Sabatini, Bernardo L (2011) Boosting of synaptic potentials and spine Ca transients by the peptide toxin SNX-482 requires alpha-1E-encoded voltage-gated Ca channels. PLoS One 6:e20939 |
| Giessel, Andrew J; Sabatini, Bernardo L (2010) M1 muscarinic receptors boost synaptic potentials and calcium influx in dendritic spines by inhibiting postsynaptic SK channels. Neuron 68:936-47 |
