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Activity regulates the nuclear import of both pre-synaptic and post-synaptic signaling molecules. Mechanisms of excitation—transcription coupling are distinct in inhibitory and excitatory neurons. Synapse-to-nucleus communication is essential for neural development, plasticity, and repair. In addition to fast electrochemical signaling, neurons employ a slower mechanism of protein transport from synapse-to-nucleus. This mechanism provides potential advantages, including the encoding of spatial information.

Many synaptonuclear signaling proteins are transported from the postsynaptic compartment to the nucleus in an activity-dependent manner. While most studies have focused on postsynaptic synaptonuclear communication, a transcriptional co-repressor, CtBP1, was recently discovered to undergo activity-dependent translocation from the presynaptic compartment to the nucleus.

Recent evidence indicates that synapse-to-nucleus communication could be cell type-specific, including the identification of a distinct mechanism of excitation-transcription coupling in inhibitory neurons. Therefore, the gene expression changes induced by AP5 in basal conditions were compared with those caused by activation of extrasynaptic NMDARs defined by Zhang et al.

Novel insights into neuronal activity-dependent gene expression by CREB

Only seven genes were bidirectionally altered by both treatments with our cutoff thresholds Fig. Gene ontology analysis was used to highlight potential biological processes regulated by NMDAR basal activity. Within the most significant AP5-dependent gene expression changes, there was a significant over-representation of genes involved in several functions, including apoptosis, synaptic function, and class IIa HDAC-related pathways Table 4.

These include significant upregulation of seven proapoptotic genes Apaf1: The identification of apoptosis-related pathways is consistent with the known role of synaptic NMDA receptor signaling in CREB-mediated neuronal survival Hardingham et al.

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HDACs are a class of enzymes that catalyze epigenetic histone modifications. Class IIa HDACs are known as transcriptional repressors associated with brain disorders, but their neuronal functions are unclear Haberland et al. Additionally, Synapsin promoter-driven GFP was included in the lentiviral vectors to enable identification of infected neurons. One week after infection, a majority of neurons expressed GFP, indicating a high efficiency of infection Fig. In control shLuc-lentivirus-infected cultures, faint cytoplasmic immunofluorescence marking endogenous HDAC4 was observed under basal conditions.

The fold change of each mRNA was normalized to vehicle treatment in cultures infected with shLuc. To address this, gene expression changes resulting from AP5 treatment were examined in the presence or absence of HDAC4. Together, these data indicate that HDAC4 plays an important role in the suppression of a subset of genes by AP5, but is not involved in baseline or PTX induction of those genes.

HDAC4 was shown to function as a transcriptional repressor and to play a role in regulating excitatory synapses Haberland et al. Therefore, we tested whether HDAC4 knockdown altered excitatory synaptic transmission. These data are consistent with a previous report Kim et al.

Novel insights into neuronal activity-dependent gene expression by CREB

Ten to 15 neurons were recorded from each condition. In contrast, control shLuc-transfected neurons showed much better survival: White arrows indicate cell bodies. The fold change is normalized to vehicle. Consistent with the microarray data, AP5 treatment significantly enhanced the expression of Apaf1, Bid, Noxa, and Puma in control shLuc-expressing neurons Fig. It is widely believed that activity-driven gene expression programs underlie long-term structural and functional changes in neurons Flavell and Greenberg, ; Loebrich and Nedivi, However, it is not well understood how neuronal gene expression patterns are maintained under conditions of basal activity, where NMDARs are known to function Sutton et al.

In this study, we took a systematic genome-wide approach to investigate the neuronal gene expression program regulated by NMDRs under conditions of basal activity. Surprisingly, the majority of genes strongly altered by AP5 in basal conditions were not significantly altered by bicuculline-induced NMDAR activity Fig. So, presumably different mechanisms regulate gene expression downstream of basal activity or bicuculline-induced stimulation of NMDARs.

While basal synaptic activity encompasses both action potentials and spontaneous presynaptic release Chawla et al. It has been suggested that spontaneous presynaptic release activates a separate pool of NMDARs with unique physiological functions compared with NMDARs activated via action potential-induced synaptic transmission Sutton et al.

It is possible that these two types of NMDAR activation recruit different downstream signaling mechanisms to regulate gene expression. HDAC4 can function as a transcriptional repressor, shuttling between the cytosol and nucleus in response to neuronal activity Zhao et al. While HDAC4 is required for neuronal function and has been implicated in a number of brain diseases Bolger and Yao, ; Haberland et al. However, in contrast to their repression, the upregulation of these genes is independent of HDAC4.

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Thus, different mechanisms likely exist downstream of NMDARs to activate or repress the same target genes. Using an unbiased microarray approach, we find that, in addition to these four genes, basal NMDAR activity controls the expression of six other apoptosis-related genes. The mRNA changes of the apoptosis-related genes were generally consistent with an enhancement of proapoptotic signaling by AP5: Nonetheless, our cultures appeared healthy up to 1 week after continuous exposure to AP5, implying that these mRNA changes are not sufficient to cause neuronal death during this time frame Fig.

The functional significance of the altered expression of apoptotic pathway components induced by AP5 remains to be addressed. Our study suggests a possibility that another gene expression program is induced simultaneously to protect neurons from apoptotic stress. Our results suggest that the nuclear localization of HDAC4 induced by low NMDAR activity serves a neuroprotective role, perhaps through suppression of a set of apoptosis-related genes Fig. Interestingly, HDAC4 has been shown to protect cerebellar neurons against apoptosis by suppressing abortive cell cycle progression Majdzadeh et al.

The relationship between these two neuroprotective mechanisms of HDAC4 remains to be tested. Further, expression of a nuclear localized HDAC4 mutant under normal activity could result in ectopic gene expression changes, leading to neuronal defects through, for example, the chronic suppression of synapse-related genes Sando et al. We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses. Skip to main content.

Highlights

Materials and Methods Neuronal cultures and drug treatments. Organotypic hippocampal slice culture, electrophysiology, and neuronal survival assay.

Post-transcriptional regulation

View inline View popup. Gene ontology and pathway analysis reveal enrichment of novel pathways in genes regulated by basal NMDAR activity Gene ontology analysis was used to highlight potential biological processes regulated by NMDAR basal activity. Pathways enriched in genes significantly altered by AP5.

Discussion It is widely believed that activity-driven gene expression programs underlie long-term structural and functional changes in neurons Flavell and Greenberg, ; Loebrich and Nedivi, Footnotes We thank Drs. The authors are employees of Genentech Inc. Correspondence should be address to either Morgan Sheng or Joshua S. Bioorg Med Chem Lett Benjamini Y , Yosef H Controlling the false discovery rate: Bourgon R , Gentleman R , Huber W Independent filtering increases detection power for high-throughput experiments. J Comp Neurol J Pharmacol Exp Ther Flavell SW , Greenberg ME Signaling mechanisms linking neuronal activity to gene expression and plasticity of the nervous system.

Annu Rev Neurosci Nat Rev Genet Cold Spring Harb Perspect Biol 3: Nat Rev Neurosci Lau D , Bading H Synaptic activity-mediated suppression of p53 and induction of nuclear calcium-regulated neuroprotective genes promote survival through inhibition of mitochondrial permeability transition.

Loebrich S , Nedivi E The function of activity-regulated genes in the nervous system. N Engl J Med Nat Rev Mol Cell Biol 9: Am J Hum Genet Arch Gen Psychiatry J Biol Chem Journal of Neuroscience Vol.