Apoptosis is an essential aspect of normal nervous system development, but when aberrantly activated, apoptosis leads to undesirable neuronal death, and such inappropriate neuronal loss is the hallmark of a variety of neurodegenerative diseases and neurological conditions, such as stroke or traumatic brain injury. The mechanisms underlying the regulation of apoptosis are beginning to be understood. Among the molecules that have recently been implicated are the histone deacetylases (HDACs). HDACs are the catalytic subunits of multiprotein complexes that deacetylate histones (11,42). The action of HDACs is opposed by histone acetyltransferases (HATs) such as CREB-binding protein and p300, which catalyze the transfer of an acetyl moiety from acetyl-coenzyme A to specific lysine residues of histones (25). Acetylation of histones relaxes the chromatin structure to a state that is transcriptionally active, while histone deacetylation transforms chromatin to a transcriptionally repressed state (25). Hence, gene expression is regulated, in part, by the balance of HDAC and HAT activities. Although best studied for their effects on histones and transcriptional activity, it is now known that HDACs and HATs regulate the acetylation of a number of other nonhistone proteins, such as p53, p65/RelA, E2F1, GATA1, and MyoD, suggesting complex functions of HDACs in different cellular processes (11,42). Precisely which cellular functions are involved is currently the subject of intense investigation.Vertebrates express at least 18 distinct HDACs, which have been grouped into three classes based on their similarities with Saccharomyces cerevisiae HDACs (11,42 Class I HDACs consist of little more than a deacetylase domain and function as transcriptional repressors. They generally are nuclear proteins expressed in most tissue and cell types (11,42). On the other hand, members of the class II HDAC subfamily display cell type-restricted patterns of expression and contain a large extended N-terminal extension with which a variety of signaling proteins interact, including MEF2, HP1␣, Bcl6, CtBP, calmodulin,42). Phosphorylation of conserved serine residues in class II HDACs by calcium/calmodulin-dependent kinase (CaMK) or protein kinase D in response to specific stimuli creates docking sites for the 14-3-3 family of protein chaperones (11,28,31,42). Binding of 14-3-3 results in the export of these HDACs from the nucleus and disrupts their interactions with transcriptional corepressor proteins, resulting in derepression of their target genes.Several classes of small-molecule HDAC inhibitors have been identified (11,29 (11,29). Because of their ability to induce the death of transformed cells, HDAC inhibitors are in clinical trials for the treatment of cancers. It is noteworthy, however, that while there are small differences in the sensitivities of individual class I and class II HDACs to different inhibitors, most of the commonly used inhibitors inhibit all HDACs efficiently. The significance of individual HDACs in any biological effect ha...