Regulating synaptic activity within a suitable working range is important for the stability of neuronal function. Homeostatic synaptic plasticity (HSP) utilizes compensatory feedback mechanisms to combat excessively low or high firing rates despite fluctuations in neuronal input, but underlying molecular pathways are not well understood. We discovered that chronic inactivity induces the formation of giant excitatory synapses specifically in proximal dendrites, with no morphological changes detected at distal synapses. These enlarged proximal dendritic structures were composed of complex clusters of synapses arranged on unusually large and elaborate dendritic spine-like protrusions, and were enriched for AMPARs and N-type calcium channels, but not NMDA receptors. Taken together, these properties were reminiscent of thorny excrescences, large branched dendritic spines of unclear function on proximal dendrites of hippocampal CA3 pyramidal neurons and mossy cells in vivo. Thus, our overarching hypotheses are that complex synapses represent the in vitro correlates of thorny excrescences, and that thorny excrescences therefore act as homeostatic control devices in independently tunable proximal dendritic zones. In this proposal, we will pursue the following Specific Aims: 1) Directly test homeostatic regulation of thorny excrescence formation in cultured neurons, hippocampal slices, and in vivo, and examine the ultrastructure of in vitro excrescences; 2) Investigate the molecular mechanisms that regulate thorny excrescence formation, focusing in particular on the role of Cav2.2 Stargazin interaction as an anchor for AMPA receptor delivery and the role of CaMKIIb in promoting assembly of this ternary complex; and 3) Analyzing the functional properties of proximal dendritic cluster synapses using electrophysiological techniques. The results obtained will be important for understanding neuronal responses to extreme changes in synaptic activity levels, and will have clinical significance for various neurological disorders involving aberrant brain activity.

Public Health Relevance

Homeostatic regulation of neuronal activity and circuits is critical for stability and optimal information processing. We have identified thorny excrescences as homeostatic regulators. Elucidating the molecular mechanisms involved in the formation and function of these structures may allow development of therapeutic strategies designed to modulate excitability in the brain in the treatment of neurological disorders involving aberrant synaptic activity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
High Priority, Short Term Project Award (R56)
Project #
1R56NS075278-01
Application #
8270434
Study Section
Synapses, Cytoskeleton and Trafficking Study Section (SYN)
Program Officer
Talley, Edmund M
Project Start
2011-08-01
Project End
2013-07-31
Budget Start
2011-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2011
Total Cost
$387,500
Indirect Cost
Name
Georgetown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
049515844
City
Washington
State
DC
Country
United States
Zip Code
20057
Queenan, Bridget N; Dunn, Raymond L; Santos, Victor R et al. (2018) Kappa opioid receptors regulate hippocampal synaptic homeostasis and epileptogenesis. Epilepsia 59:106-122
Queenan, B N; Lee, K J; Tan, H et al. (2016) Mapping homeostatic synaptic plasticity using cable properties of dendrites. Neuroscience 315:206-16
Lee, Kea Joo; Queenan, Bridget N; Rozeboom, Aaron M et al. (2013) Mossy fiber-CA3 synapses mediate homeostatic plasticity in mature hippocampal neurons. Neuron 77:99-114
Queenan, Bridget N; Lee, Kea Joo; Pak, Daniel T S (2012) Wherefore art thou, homeo(stasis)? Functional diversity in homeostatic synaptic plasticity. Neural Plast 2012:718203