Enrichment of DARPP- 32-positive neurons will be required for a definitive study of the effects of HDACi��s and BDNF on acetylation of the ppp1r1b promoter region. It has recently been reported that many striatalenriched genes are characterized by relatively increased H3 acetylation in coding portions rather than in the promoter, and that this correlation persists in the presence of mutant huntingtin and HDAC inhibitors. Moreover, Egr-1 can modify acetylation status around its binding sites. This may also contribute to our inability to consistently demonstrate an increase in bound acH3 after HDACi treatment around the promoter, and it will be important in the future to survey the entire ppp1r1b gene in a setting of enrichment for DARPP-32-positive neurons. In vivo, striatal BDNF is largely derived via anterograde transport from the cortex, and only late death of MSNs in aged mice occurs following prenatal knockout of cortical BDNF. BDNF is, however, required for the maturation of MSNs in vivo as demonstrated by the absence of calbindin and the delayed Vorinostat appearance of DARPP-32 in the BDNF-null striatum and the presence of abnormal dendritic and spine growth in MSNs in mice with a conditional forebrain deletion. In most studies, exogenous BDNF does not have an impact on MSN survival in vitro. BDNF requires Egr-1 for induction of DARPP-32. Nerve growth factor and Egr-1 induce Nab2 in certain contexts, but this is the first report of induction of Nab2 by BDNF. Originally identified as an Egr-1 co-repressor, it was later shown that Nab2 can also act as an Egr-1 co-activator, a function which is also context specific. It is possible, therefore, that the interaction between Egr-1 and Nab2 could serve to mediate both up-regulation and down-regulation of genes that occur during MSN differentiation. Moreover, and not surprisingly, it highlights the complicated pathways via which a growth factor and chromatin modifying agent alter expression level of a specific gene. It is consistent with the notion that induction of DARPP-32 by HDACi��s may not include increased acetylation at specific sites within the gene and may be indirect. These data may be applicable to the goal of converting hES and hIPS cells to MSNs. The most widely used differentiation program to date is that of Aubry et al in which neural precursors are treated with BDNF, and then with BDNF and VPA for terminal differentiation into MSN-like neurons. It is possible, therefore, that a combination of BDNF and VPA is actually inhibiting aspects of differentiation, particularly if DARPP-32 is used as the marker. A more robust differentiation protocol was recently reported in which VPA is added first in isolation, and is removed when BDNF is added days later, but perhaps the most robust terminal differentiation occurs in the presence of BDNF without addition of VPA. Going forward, therefore, it will be prudent to assay multiple MSN markers in order to label the neuron as terminally differentiated. Similar issues are relevant to the search for HD treatments that do not include cell replacement. Significant effort is being expended on identification of agents to pharmacologically manipulate the BDNF/TrkB pathway and HDAC activity. As with most neurodegenerative diseases, poly-pharmacy will likely be required, highlighting the need to Niraparib determine interactions between potential treatments. Convincing evidence indicates that the infiltration of monocyte-derived cells from the periphery into the CNS and perivascular spaces may help restrict amyloid deposition and prevent cognitive decline. These studies have shown that bone marrow-derived cells or monocytes are recruited to the brain and can restrict amyloid plaque deposition in AD transgenic mice.