Rapid modulation of spine morphology by the 5-HT2A serotonin receptor through kalirin-7 signaling

Kelly A. Jones, Deepak P. Srivastava, John Allen, Ryan T. Strachan, Bryan L. Roth, Peter Penzes

Research output: Contribution to journalArticle

95 Scopus citations

Abstract

The 5-HT2A serotonin receptor is the most abundant serotonin receptor subtype in the cortex and is predominantly expressed in pyramidal neurons. The 5-HT2A receptor is a target of several hallucinogens, antipsychotics, anxiolytics, and antidepressants, and it has been associated with several psychiatric disorders, conditions that are also associated with aberrations in dendritic spine morphogenesis. However, the role of 5-HT 2A receptors in regulating dendritic spine morphogenesis in cortical neurons is unknown. Here we show that the 5-HT2A receptor is present in a subset of spines, in addition to dendritic shafts. It colocalizes with PSD-95 and with multiple PDZ protein-1 (MUPP1) in a subset of dendritic spines of rat cortical pyramidal neurons. MUPP1 is enriched in postsynaptic density (PSD) fractions, is targeted to spines in pyramidal neurons, and enhances the localization of 5-HT2A receptors to the cell periphery. 5-HT 2A receptor activation by the 5-HT2 receptor agonist DOI induced a transient increase in dendritic spine size, as well as phosphorylation of p21-activated kinase (PAK) in cultured cortical neurons. PAK is a downstream target of the neuronal Rac guanine nucleotide exchange factor (RacGEF) kalirin-7 that is important for spine remodeling. Kalirin-7 regulates dendritic spine morphogenesis in neurons but its role in neuromodulator signaling has not been investigated. We show that peptide interference that prevents the localization of kalirin-7 to the postsynaptic density disrupts DOI-induced PAK phosphorylation and spine morphogenesis. These results suggest a potential role for serotonin signaling in modulating spine morphology and kalirin-7's function at cortical synapses.

Original languageEnglish (US)
Pages (from-to)19575-19580
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number46
DOIs
StatePublished - Nov 17 2009
Externally publishedYes

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Keywords

  • GPCR
  • Neuromodulator
  • PAK
  • Rac
  • Synapse

ASJC Scopus subject areas

  • General

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