No abstract

No abstract

Thermal control establishment develops during a critical period by alterations in cellular properties in the frontal hypothalamus. These alterations may be modulated by the epigenetic code that determines the repertoire of transcribed proteins. Here we demonstrate transient changes in the expression of brain-derived neurotrophic factor (Bdnf) during both thermal conditioning and re-exposure of conditioned chicks to heat stress, relative to their age-matched naive counterparts. These changes coincide with changes in CpG methylation pattern in the avian Bdnf promoter region. Reduction in methylation during heat conditioning was observed at a cAMP response element-binding (CREB) site which coincided with both elevation in phospho-CREB levels and its binding to the Bdnf promoter. At the same time, an increase in methylation was observed at two other CpG sites, accompanied by elevation of the DNA methyltransferase 3a (DNMT3a) expression. DNMT3a was also found to bind to the two elevated methyl CpG sites, but not to the CREB binding site. These data suggest that complex and dynamic changes in DNA methylation are involved in the regulation of Bdnf expression during thermotolerance acquisition.

Calcium signaling critical to neural functions is mediated through Ca(2+) channels localized on both the plasma membrane and intracellular organelles such as endoplasmic reticulum. Whereas Ca(2+) influx occurs via the voltage- or/and ligand-sensitive Ca(2+) channels, Ca(2+) release from intracellular stores that amplifies further the Ca(2+) signal is thought to be involved in more profound and lasting changes in neurons. The ryanodine receptor, one of the two major intracellular Ca(2+) channels, has been an important target for studying Ca(2+) signaling in brain functions, including learning and memory, due to its characteristic Ca(2+)-induced Ca(2+) release. In this study, we report regional and cellular distributions of the type-2 ryanodine receptor (RyR2) mRNA in the rat brain, and effects of spatial learning on RyR2 gene expression at mRNA and protein levels in the rat hippocampus. Using in situ hybridization, reverse transcription polymerase chain reaction, and ribonuclease protection assays, significant increases in RyR2 mRNA were found in the hippocampus of rats trained in an intensive water maze task. With immunoprecipitation and immunoblotting, protein levels of RyR2 were also demonstrated to be increased in the microsomal fractions prepared from hippocampi of trained rats. These results suggest that RyR2, and hence the RyR2-mediated Ca(2+) signals, may be involved in memory processing after spatial learning. The increases in RyR2 mRNA and protein at 12 and 24 h after training could contribute to more permanent changes such as structural modifications during long-term memory storage. Zhao, W., Meiri, N., Xu, H., Cavallaro, S., Quattrone, A., Zhang, L., Alkon, D. A. Spatial learning induced changes in expression of the ryanodine type II receptor in the rat hippocampus.

The effects of changing NMDA receptor subunit composition on synaptic plasticity in the hippocampus were analyzed by creating transgenic mice overexpressing NR2D, a predominantly embryonic NMDA receptor subunit. NMDA-evoked currents in the transgenic mice had smaller amplitudes and slower kinetics. The transgenics also displayed age-dependent deficits in synaptic plasticity in area CA1 of the hippocampus. Long-term depression was selectively impaired in juvenile mice when NR2D overexpression was moderate. In mature mice, overexpression of NR2D was associated with a reduction of both NR2B and Ca 2ϩ -independent activity of Ca 2ϩ -and calmodulin-dependent protein kinase II. These biochemical changes were correlated with a marked impairment of NMDAdependent long-term potentiation, but spatial behavior was normal in these mice. These results show that the developmental regulation of NMDA receptor subunit composition alters the frequency at which modification of synaptic responses occur after afferent stimulation.Key words: hippocampus; NMDA receptor; long-term potentiation; long-term depression; water maze; transgenic mice Long-term potentiation (LTP) and long-term depression (LTD) are two forms of plasticity that have been studied extensively in area CA1 of the hippocampus. Both LTP and LTD, triggered by either high-frequency stimulation (HFS) or low-frequency stimulation (L FS) of the Schaffer collateral CA1 synapses, involve calcium influx through NMDA receptors (Collingridge et al., 1983;Dudek and Bear, 1992;Mulkey and Malenka, 1992). A recent analysis of mice genetically modified to express higher levels of the C a 2ϩ -independent form of C a 2ϩ -and calmodulindependent protein kinase II␣ (C aM K II␣) suggests that the threshold of stimulus frequency required to elicit an increase or decrease of synaptic strength can be modulated by the amount of Ca 2ϩ -independent activity of C aM K II (Mayford et al., 1995). This work provides evidence that LTP and LTD share the same downstream pathway from the NMDA receptor activation and that C aM K II is one of the regulators of the Hebbian synaptic modification. A theoretical study has pointed out that the Ca 2ϩ increase in the postsynaptic site after HFS can be altered dramatically by several factors, including NMDA receptor channel kinetics (Gold and Bear, 1994). This model predicts that a change in the decay constant of NMDA receptor channels of 100 msec can induce a 10-fold difference in the peak C a 2ϩ concentration in the dendritic spine. Thus, modulation of NMDA receptor properties might also be an efficient site for the frequency-dependent regulation of synaptic modification. The NMDA receptors in the brain are complexes of NR1 and NR2 subunits . The NR1 subunit is essential for NMDA receptor function and is expressed ubiquitously in the brain (Moriyoshi et al., 1991;Flint et al., 1997). In contrast, NR2A-D subunits have distinct expression profiles that are regulated both developmentally and regionally (Kutsuwada et al., 1992;Watanabe et al., 1992;Monyer et al., ...