Having identified a mechanism of cocaine-dependent regulation of HDAC5, the authors seized the opportunity to test the biological requirements for HDAC5 regulation in behavioral adaptations to cocaine. Using stereotaxic injection of viruses into the NAc of adult mice, the authors found that overexpression of the S279A HDAC5 mutant, which cannot be phosphorylated at S279, inhibited CPP.

These findings are consistent with previous evidence implicating HDAC5 Navitoclax mouse in the inhibition of reward (Renthal et al., 2007). However, they further suggest that regulation of HDAC5 phosphorylation at S279 is an essential part of this mechanism. Unfortunately, how the S279A mutation disrupts HDAC5 function in CPP is not entirely clear, since the authors uncovered no differences in nucleocytoplasmic shuttling between this mutant and wild-type HDAC5 in cultured striatal neurons. Though it remains possible that mutation of S279 to alanine could selectively affect HDAC5 trafficking in adult striatal neurons in vivo, an alternative explanation is that this mutation affects the ability of HDAC5 to act as a corepressor through mechanisms that remain to be identified. The work of Taniguchi and colleagues substantially enhances understanding of the molecular players that lie between exposure to cocaine Ion Channel Ligand Library in vitro and a key enzyme

that regulates histone acetylation. However, the specific findings of this study also raise important new questions about the downstream consequences of HDAC5 regulation for behavior. For example, Renthal and collaborators identified a large set of gene transcripts that were dysregulated in Hdac5 knockout mice compared with their wild-type littermates ( Renthal et al., 2007); however, whether these are direct or indirect targets of HDAC5 regulation remains

unknown. Taniguchi and colleagues Phosphoprotein phosphatase propose that repression of MEF2-dependent transcription is an essential function of HDAC5 and point out that the phenotype of the HDAC5 S279A mutant in CPP is opposite of that seen upon viral overexpression of a constitutively active MEF2 ( Pulipparacharuvil et al., 2008). However, Renthal reported that deletion of the MEF2 binding domain in HDAC5 had no effect on HDAC5-dependent inhibition of CPP ( Renthal et al., 2007). Thus, further experiments will be needed to clarify the gene regulatory pathways that require HDAC5. It will also be important to determine which striatal neuron classes utilize HDAC5 regulation. Given the requirement for cAMP elevation in the cascade that leads to S279 dephosphorylation, it is likely that the D1-class dopamine receptor-expressing medium spiny neurons are a major site of HDAC5 regulation in this study.