Presynaptic Rac1 in the hippocampus selectively regulates working memory.

Autor:	Kim J; Department of Cell Biology, Duke University School of Medicine, Durham, United States., Bustamante E; Department of Cell Biology, Duke University School of Medicine, Durham, United States., Sotonyi P; Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary., Maxwell N; Department of Cell Biology, Duke University School of Medicine, Durham, United States., Parameswaran P; Department of Cell Biology, Duke University School of Medicine, Durham, United States., Kent JK; Department of Cell Biology, Duke University School of Medicine, Durham, United States., Wetsel WC; Department of Cell Biology, Duke University School of Medicine, Durham, United States.; Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, United States.; Mouse Behavioral and Neuroendocrine Analysis Core Facility, Duke University School of Medicine, Durham, United States.; Department of Neurobiology, Duke University School of Medicine, Durham, United States., Soderblom EJ; Department of Cell Biology, Duke University School of Medicine, Durham, United States.; Proteomics and Metabolomics Shared Resource and Center for Genomic and Computational Biology, Duke University School of Medicine, Durham, United States., Rácz B; Department of Anatomy and Histology, University of Veterinary Medicine, Budapest, Hungary., Soderling SH; Department of Cell Biology, Duke University School of Medicine, Durham, United States.; Department of Neurobiology, Duke University School of Medicine, Durham, United States.
Jazyk:	angličtina
Zdroj:	ELife [Elife] 2024 Jul 24; Vol. 13. Date of Electronic Publication: 2024 Jul 24.
DOI:	10.7554/eLife.97289
Abstrakt:	One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear. Here, we show that spatial working memory in mice is selectively impaired following the expression of a genetically encoded Rac1 inhibitor at presynaptic terminals, while longer-term cognitive processes are affected by Rac1 inhibition at postsynaptic sites. To investigate the regulatory mechanisms of this presynaptic process, we leveraged new advances in mass spectrometry to identify the proteomic and post-translational landscape of presynaptic Rac1 signaling. We identified serine/threonine kinases and phosphorylated cytoskeletal signaling and synaptic vesicle proteins enriched with active Rac1. The phosphorylated sites in these proteins are at positions likely to have regulatory effects on synaptic vesicles. Consistent with this, we also report changes in the distribution and morphology of synaptic vesicles and in postsynaptic ultrastructure following presynaptic Rac1 inhibition. Overall, this study reveals a previously unrecognized presynaptic role of Rac1 signaling in cognitive processes and provides insights into its potential regulatory mechanisms. Competing Interests: JK, EB, PS, NM, PP, JK, WW, ES, BR, SS No competing interests declared (© 2024, Kim et al.)
Databáze:	MEDLINE
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