Cocaine regulates MEF2 to control synaptic and behavioral plasticity.
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.
Pulipparacharuvil
Suprabha
S
Department of Psychiatry, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9127, USA.
Renthal
William
W
Hale
Carly F
CF
Taniguchi
Makoto
M
Xiao
Guanghua
G
Kumar
Arvind
A
Russo
Scott J
SJ
Sikder
Devanjan
D
Dewey
Colleen M
CM
Davis
Maya M
MM
Greengard
Paul
P
Nairn
Angus C
AC
Nestler
Eric J
EJ
Cowan
Christopher W
CW