HDAC activity is required for BDNF to increase dendritic spine density and quantal neurotransmitter release onto CA1 pyramidal neurons

L. POZZO-MILLER, F. LUBIN, S. CAMPBELL, G. CALFA

Washington

Congreso; Society for Neroscience - Neuroscience 2008; 2008

BDNF is a potent modulator of synaptic structure and function, exerting its actions across a widespread time window. Considering that long-tem actions of BDNF involve gene transcription and its well-described role in synaptic plasticity and learning and memory processes, and the recent observations of epigenetic changes for those same events, we hypothesized that chromatin remodeling was required for the synaptic effects of BDNF. Since chromatin remodeling by histone acetylation is one of the epigenetic mechanisms responsible for transcriptional regulation, we tested whether inhibition of histone deacetylases (HDAC) affected BDNF actions. Hippocampal slice cultures from postnatal rat hippocampus were exposed to hrBDNF (250ng/mL; 48hs) in presence and absence of trichostatin A (TSA, 1.65μM). As previously shown (Tyler and Pozzo-Miller 2001), long-term BDNF exposure increased the frequency of AMPAR-mediated mEPSCs in CA1 pyramidal neurons, without affecting their amplitude or individual kinetics. Consistent with a requirement of histone modifications, this effect was significantly reduced by co-incubation with TSA. However, HDAC inhibition per se had no consequences on mEPSC frequency, amplitude or kinetics. Similar observations were obtained when recording mEPSCs from CA1 neurons in acute hippocampal slices exposed to TSA for 15min. Considering that the increased mEPSC frequency caused by BDNF resulted from both enhanced transmitter release and a higher density of excitatory spine synapses (Tyler and Pozzo-Miller 2001), we next quantified dendritic spine density as a surrogate for excitatory synapses. As previously shown, BDNF increased spine density in CA1 pyramidal neurons, an effect completely prevented by co-incubation with TSA. Consistent with the observations on quantal transmitter release, TSA by itself did not affect spine density. Taken together, these results suggest that the transcriptional program initiated by long-term BDNF exposure requires chromatin remodeling such as histone acetylation. Future studies will address whether enhanced transmitter release is a consequence of structural remodeling of release sites, and potential involvement of other epigenetic mechanisms, such as DNA methylation.