title: Cocaine regulates MEF2 to control synaptic and behavioral plasticity.
abstract: Repeated exposure to cocaine causes sensitized behavioral responses and increased dendritic spines on medium spiny neurons of the nucleus accumbens (NAc). We find that cocaine regulates myocyte enhancer factor 2 (MEF2) transcription factors to control these two processes in vivo. Cocaine suppresses striatal MEF2 activity in part through a mechanism involving cAMP, the regulator of calmodulin signaling (RCS), and calcineurin. We show that reducing MEF2 activity in the NAc in vivo is required for the cocaine-induced increases in dendritic spine density. Surprisingly, we find that increasing MEF2 activity in the NAc, which blocks the cocaine-induced increase in dendritic spine density, enhances sensitized behavioral responses to cocaine. Together, our findings implicate MEF2 as a key regulator of structural synapse plasticity and sensitized responses to cocaine and suggest that reducing MEF2 activity (and increasing spine density) in NAc may be a compensatory mechanism to limit long-lasting maladaptive behavioral responses to cocaine.
authors.affiliation: Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9127, USA.
authors.forename: Suprabha
authors.initials: S
authors.lastname: Pulipparacharuvil
authors.forename: William
authors.initials: W
authors.lastname: Renthal
authors.forename: Carly F
authors.initials: CF
authors.lastname: Hale
authors.forename: Makoto
authors.initials: M
authors.lastname: Taniguchi
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.forename: Arvind
authors.initials: A
authors.lastname: Kumar
authors.forename: Scott J
authors.initials: SJ
authors.lastname: Russo
authors.forename: Devanjan
authors.initials: D
authors.lastname: Sikder
authors.forename: Colleen M
authors.initials: CM
authors.lastname: Dewey
authors.forename: Maya M
authors.initials: MM
authors.lastname: Davis
authors.forename: Paul
authors.initials: P
authors.lastname: Greengard
authors.forename: Angus C
authors.initials: AC
authors.lastname: Nairn
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Nestler
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cowan