My lab pioneered the study of homeostatic plasticity in neocortical neurons and networks. Recently we found that neocortical neurons both in vitro and in vivo have a """"""""firing rate set point"""""""" (FRSP) around which they regulate their average firing. This is accomplished through a set of homeostatic plasticity mechanisms, including synaptic scaling and homeostatic regulation of intrinsic excitability, that act to restore excitability when it is perturbed by changes in sensory drive or synaptic input. We have made significant inroads into understanding the molecular signaling pathways and machinery that accomplishes this homeostatic regulation of firing;in particular, we know that cell-autonomous changes in average neuronal firing that modulate somatic calcium influx lead to changes in signaling through the calcium-dependent kinase CaMKIV, and this in turn produces transcription-dependent homeostatic alterations in the surface expression of ion channels and glutamate receptors. Despite this progress, it remains largely mysterious how neocortical neurons (or any other cell type) build a stable firing-rate set-point out of calcium-dependent signaling pathways. Here we wish to test the central hypotiiesis that FRSP in neocortical neurons is the equilibrium point of opposing calcium-dependent signaling pathways that regulate excitability, and that this basic principle for how to build a stable FRSP wdll generalize to fundamentally different cell types. We have three major aims: i) test the prediction that FRSP can be modulated by altering the strength of specific calcium-dependent signaling pathways, such as CaMKIV;2) Identify other elements that act in opposition to CaMKIV and together comprise the FRSP, and 3) determine which homeostatic effectors are downstream of CaMKIV to generate homeostatic compensation. This project wdll illuminate the mechanistic underpinnings of a fundamental aspect of neuronal physiology, and through collaborative work the Other Pis on this Program Project.

Public Health Relevance

Maintaining an activity set-point is critical for brain health, yet we currently have no idea how such set-points are constructed. Identifying the molecular constituents that comprise neocortical set- points wdll allow us to determine how set points work normally, and how malfunction of these set- points might contribute to a variety of neurological and neurodevelopmental disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Program Projects (P01)
Project #
5P01NS079419-02
Application #
8743091
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Brandeis University
Department
Type
DUNS #
City
Waltham
State
MA
Country
United States
Zip Code
02453
Joseph, Annelise; Turrigiano, Gina G (2017) All for One But Not One for All: Excitatory Synaptic Scaling and Intrinsic Excitability Are Coregulated by CaMKIV, Whereas Inhibitory Synaptic Scaling Is Under Independent Control. J Neurosci 37:6778-6785
O'Toole, Sean M; Ferrer, Monica M; Mekonnen, Jennifer et al. (2017) Dicer maintains the identity and function of proprioceptive sensory neurons. J Neurophysiol 117:1057-1069
Abraira, Victoria E; Kuehn, Emily D; Chirila, Anda M et al. (2017) The Cellular and Synaptic Architecture of the Mechanosensory Dorsal Horn. Cell 168:295-310.e19
Cannon, Jonathan; Miller, Paul (2017) Stable Control of Firing Rate Mean and Variance by Dual Homeostatic Mechanisms. J Math Neurosci 7:1
Choy, Julian M C; Suzuki, Norimitsu; Shima, Yasuyuki et al. (2017) Optogenetic Mapping of Intracortical Circuits Originating from Semilunar Cells in the Piriform Cortex. Cereb Cortex 27:589-601
Williams, Alex H; O'Donnell, Cian; Sejnowski, Terrence J et al. (2016) Dendritic trafficking faces physiologically critical speed-precision tradeoffs. Elife 5:
Gjorgjieva, Julijana; Drion, Guillaume; Marder, Eve (2016) Computational implications of biophysical diversity and multiple timescales in neurons and synapses for circuit performance. Curr Opin Neurobiol 37:44-52
Crittenden, Jill R; Tillberg, Paul W; Riad, Michael H et al. (2016) Striosome-dendron bouquets highlight a unique striatonigral circuit targeting dopamine-containing neurons. Proc Natl Acad Sci U S A 113:11318-11323
O'Leary, Timothy; Marder, Eve (2016) Temperature-Robust Neural Function from Activity-Dependent Ion Channel Regulation. Curr Biol 26:2935-2941
Steinmetz, Celine C; Tatavarty, Vedakumar; Sugino, Ken et al. (2016) Upregulation of ?3A Drives Homeostatic Plasticity by Rerouting AMPAR into the Recycling Endosomal Pathway. Cell Rep 16:2711-2722

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