Phospho-regulation as a driver of inhibitory synapse function

NIH RePORTER · NIH · F32 · $65,994 · view on reporter.nih.gov ↗

Abstract

Phosphorylation has long been studied as a way to shape protein function after translation. In the brain, phosphorylation has emerged as one of the most efficient ways to transduce activity-dependent information to altered synaptic function. Extensive literature supports phosphorylation as an essential component of signal transduction at glutamatergic excitatory postsynapses within the CNS. Emerging evidence, however, demonstrates that GABAergic inhibitory postsynapses also undergo activity dependent plasticity. Based on limited candidate studies, a handful of GABAergic proteins have recently been shown to be phosphorylated at inhibitory synapses. While this supports phosphorylation as a likely mechanism to modulate inhibitory synapses, an in-depth analysis of how phosphorylation is coupled to inhibitory synapses function has not been attempted. Moreover, it is still unclear as to which kinases are present and therefore act at inhibitory synapses. Thus, the inhibitory synaptic phospho-proteome is currently a “black box”, which is a significant barrier to understanding how activity modifies inhibition important for shaping experience-dependent brain function. Here, I propose to use a cutting edge in vivo chemico-genetic approach to identify phosphorylated proteins at inhibitory synapses in combination with CRISPR-depletion, optogenetics, electrophysiology and imaging to understand how kinases orchestrate the complex yet fundamental workings of the inhibitory synapse.

Key facts

NIH application ID
10187339
Project number
1F32NS117676-01A1
Recipient
DUKE UNIVERSITY
Principal Investigator
Alicia Mae Purkey
Activity code
F32
Funding institute
NIH
Fiscal year
2021
Award amount
$65,994
Award type
1
Project period
2021-04-01 → 2022-03-31