Mechanisms for regulating the efficacy of synaptic coupling, or synaptic strength, between neurons are required for critical brain functions such as learning and memory. The process of altering synaptic strength between neurons, broadly termed synaptic plasticity, is impaired or absent in numerous neuropsychiatric disorders and diseases. A key mechanism for one of the most robust forms of synaptic plasticity, long-term potentiation, is the addition of AMPA-type neurotransmitter receptors from internal vesicular stores known as recycling endosomes (REs), to the postsynaptic membrane. Recent work has demonstrated that a large fraction of dendritic spines, the major sites of excitatory synaptic contact, contain REs and that these REs undergo fusion with the spine plasma membrane to deposit a stable pool of AMPA receptors at or near the synapse in response to plasticity-inducing activity. These data indicate that spine REs are poised for local delivery of plasticity factors to activated synapses, but many fundamental questions remain. For example, why these organelles are found in some spines but not others, how they are mobilized to fuse with the plasma membrane by plasticity-inducing stimuli, and how fusion contributes to synaptic function and plasticity are important issues we propose to address in this project.
In Aim1 we will address whether the history of synaptic activity influences the distribution REs at individual synapses and/or their AMPA receptor content.
In Aim2 we will determine whether plasticity at individual synapses directly scales with spine RE content.
In Aim3 we will dissect the second messengers and signaling molecules that couple synaptic activity to spine RE fusion. Combined, these independent but complementary aims will greatly advance our understanding of fundamental forms of neuronal plasticity and inform future efforts in determining how and why plasticity is disrupted in numerous neuropsychiatric disorders and diseases including Alzheimer's, autism, schizophrenia and addiction.
Regulated changes in the efficiency of synaptic coupling in the central nervous system, a process known as synaptic plasticity, is absolutely critical for normal cognitive function. This proposal investigates the cellular and molecular mechanisms responsible for important forms of plasticity involved in learning and memory that are disrupted in numerous neuropsychiatric disorders and diseases including autism, addiction, schizophrenia, and Alzheimer's.
|Sinnen, Brooke L; Bowen, Aaron B; Forte, Jeffrey S et al. (2017) Optogenetic Control of Synaptic Composition and Function. Neuron 93:646-660.e5|
|Hiester, Brian G; Bourke, Ashley M; Sinnen, Brooke L et al. (2017) L-Type Voltage-Gated Ca2+ Channels Regulate Synaptic-Activity-Triggered Recycling Endosome Fusion in Neuronal Dendrites. Cell Rep 21:2134-2146|
|Bowen, Aaron B; Bourke, Ashley M; Hiester, Brian G et al. (2017) Golgi-independent secretory trafficking through recycling endosomes in neuronal dendrites and spines. Elife 6:|
|Zimmerman, Seth P; Hallett, Ryan A; Bourke, Ashley M et al. (2016) Tuning the Binding Affinities and Reversion Kinetics of a Light Inducible Dimer Allows Control of Transmembrane Protein Localization. Biochemistry 55:5264-71|
|Sinnen, Brooke L; Bowen, Aaron B; Gibson, Emily S et al. (2016) Local and Use-Dependent Effects of ?-Amyloid Oligomers on NMDA Receptor Function Revealed by Optical Quantal Analysis. J Neurosci 36:11532-11543|
|Carrodus, Nissa L; Teng, Kathleen Sue-Lyn; Munro, Kathryn M et al. (2014) Differential labeling of cell-surface and internalized proteins after antibody feeding of live cultured neurons. J Vis Exp :e51139|
|Taslimi, Amir; Vrana, Justin D; Chen, Daniel et al. (2014) An optimized optogenetic clustering tool for probing protein interaction and function. Nat Commun 5:4925|
|Tucker, Chandra L; Vrana, Justin D; Kennedy, Matthew J (2014) Tools for controlling protein interactions using light. Curr Protoc Cell Biol 64:17.16.1-20|
|Chen, Daniel; Gibson, Emily S; Kennedy, Matthew J (2013) A light-triggered protein secretion system. J Cell Biol 201:631-40|
|Fox, Philip D; Haberkorn, Christopher J; Weigel, Aubrey V et al. (2013) Plasma membrane domains enriched in cortical endoplasmic reticulum function as membrane protein trafficking hubs. Mol Biol Cell 24:2703-13|