, 2005, 2008). Mature miRNA present in synaptoneurosome fractions of adult brain tissue derives at least in part from processing of local precursors (Lugli et al., 2008). Evidence suggests that NMDAR activation PS-341 purchase results in the proteolytic liberation of Dicer from the postsynaptic density and

subsequent activation of its RNAase III activity (Lugli et al., 2005). Mature miRNAs regulated by this mechanism should be rapidly elevated at synaptic sites following NMDAR activation and LTP induction, while the corresponding precursor levels should decrease. Such a pattern of regulation was not observed in the present study, but our measurements of miRNA expression in whole dentate gyrus homogenates (rather than synaptic fractions) cannot be used to address the question of local precursor processing in LTP. check details Taken together, however, these studies have revealed an unexpected regulation of the mature miRNA expression by NMDAR-dependent and transcription-independent mechanisms. Coordinate action of many miRNAs is crucial for biological processes,

such as cell fate determination and apoptosis. Co-transcriptional regulation is one way by which such coordination is thought to be achieved (Cheng et al., 2007; He et al., 2007). Evidence suggests that miR-132 and -212 are co-transcriptionally regulated from a stable intron of a cryptic non-coding RNA (Vo et al., 2005). An important common target of miR-132 and -212 is the Rac/Rho-family p250GAP. In cultured hippocampal neurons, activity-dependent Bay 11-7085 expression of miR-132 regulates dendritic morphogenesis by decreasing synthesis of p250GAP (Vo et al., 2005; Wayman et al., 2008). The transcription of miR-132 in this context is CREB dependent, and stimulated by NMDAR and brain-derived neurotrophic factor (BDNF)-activated

signaling pathways. In vitro studies also indicate a key role for miR-132 transcription in the homeostatic regulation of MeCP2 during neural development (Klein et al., 2007). The present work on LTP in the adult gyrus shows that transcription of pri-miR-132 and -212 is strongly dependent on mGluR rather than NMDAR activation. Changes in mature miR-132 and miR-212 during LTP reflected the opposing effects of mGluR and NMDAR signaling. Interestingly, while net levels of mature miRNA were significantly increased, no changes in the expression of p250GAP or MeCP2 protein were detected. Taken together, the results suggest that transcriptional regulation of miR-132/212 and its impact on target protein expression differs substantially between the developmental setting of embryonic neurons and LTP in the adult brain. The present study gives the first insights into regulation of miRNA expression during LTP in the adult mammalian brain.