Neuronal activity-regulated gene transcription in synapse development and cognitive function

Abstract

Activity-dependent plasticity of vertebrate neurons allows the brain to respond to its environment. During brain development, both spontaneous and sensory-driven neural activity are essential for instructively guiding the process of synapse development. These effects of neuronal activity are transduced in part through the concerted regulation of a set of activity-dependent transcription factors that coordinate a program of gene expression required for the formation and maturation of synapses. Here we review the cellular signaling networks that regulate the activity of transcription factors during brain development and discuss the functional roles of specific activity-regulated transcription factors in specific stages of synapse formation, refinement, and maturation. Interestingly, a number of neurodevelopmental disorders have been linked to abnormalities in activity-regulated transcriptional pathways, indicating that these signaling networks are critical for cognitive development and function.

Figure 1.

Mechanisms that regulate activity-dependent transcription of Fos. The top panel represents Fos in the absence of activity and the bottom panel shows Fos following a synaptic stimulus that activates intracellular calcium (Ca²⁺) signaling. In the absence of activity, Fos is primed for activation by the association of the transcriptional activators CREB with the cAMP/calcium response element (CRE) and Elk-1/SRF with the serum response element (SRE). The promoter is also bound by RNA polymerase II (POLII), and has the presence of histone H3 lysine 4 trimethylation (me3) at promoter histones. However, the gene is held in a repressed state by the presence of histone deacetylases (HDACs) recruited to Elk-1 and the Retinoblastoma (Rb)-BRG1-CREST complex, which binds the zinc-finger transcription factor Sp1 at the Retinoblastoma control element (RCE). Following activation of calcium-dependent signaling pathways, the histone acetyltransferase CBP is recruited to phosphorylated (P) CREB, inducing local histone acetylation (AC). Calcineurin-dependent dephosphorylation of Rb releases the HDACs, which are then exported from the nucleus in a phosphorylation-dependent manner. RNA polymerase II and CBP are also recruited to histone H3 lysine 4 monomethylated (me1) enhancer regions that are prebound by SRF and CREB and hypothesized to interact with the Fos promoter through long-distance looping. Transcription of Fos mRNA and of eRNAs is then induced (green wavy lines).

Figure 2.

Activity-dependent transcription factor regulation of distinct stages in synapse development. Neurite outgrowth promotes contacts between axons (left) and dendrites (right) that define potential synaptic target fields. At some of these points of contact, actin-rich dendritic spines develop at sites opposed to axon terminals to form excitatory synapses. These synapses either stabilize and strengthen, or they are eliminated. Finally, excitatory synapses are balanced by the formation of inhibitory synapses (pictured on the dendritic shaft). Calcium signaling (Ca) is involved at each of these steps.

Figure 3.

Ube3a/Arc-dependent dysregulation of activity-induced AMPA-type glutamate receptor trafficking in Angelman syndrome. (A) Synaptic activation of AMPA-type (AMPAR) and NMDA-type (NMDAR) glutamate receptors induces the rapid MEF2-dependent transcription of Arc and the slower MEF2-dependent transcription of Ube3a in the nucleus. Transcriptional regulation of Arc is initiated by calcium influx through both NMDARs and voltage-sensitive calcium channels (VSCCs). This plasma membrane signal is transmitted to the nucleus through the calcium-dependent activation of multiple intracellular signaling intermediates, including the MAP kinase cascade and actin signaling pathways that subsequently modulate nuclear transcription factor function. The Arc promoter is coregulated by multiple activity-responsive transcription factors including MEF2, CREB, SRF, and the SRF cofactor Mal. Other transcription factors that contribute to regulation of Ube3a remain to be identified (X). (B) At synapses, Arc protein contributes to endocytosis of AMPA-type glutamate receptors from the cell surface. In wild-type (WT) neurons, Arc levels are kept in check by Ube3A-dependent proteosomal degradation. In Ube3a knockout neurons, elevated levels of Arc lead to abnormally high levels of AMPA-type glutamate receptor internalization, impairing synaptic strength.

Figure 4.

Model for a common activity-regulated transcriptional network underlying synapse dysfunction in neurodevelopmental diseases. The yellow boxes show four neurodevelopmental diseases associated with disrupted synapse development: Angelman syndrome, Fragile X syndrome (OMIM 300624), Rett syndrome, and autism. Each disease is shown next to a gene product implicated in disease pathogenesis. The dotted line around Autism depicts the hypothetical nature of the link between autism and Npas4 as discussed in the text. Green arrows show positive relationships between proteins or processes in the model; the red bars show inhibitory relationships. The dotted black lines indicate more complex relationships. For example Arc is implicated in endocytosis of AMPA-type glutamate receptors (AMPARs) from the plasma membrane, suggesting a negative relationship between these two proteins (Chowdhury et al. 2006); however, Arc is also required for some forms of LTP (McCurry et al. 2010), during which AMPARs are added to the synapse. The dotted line between MeCP2 and inhibitory synapses represents the observation that GABAergic synapse numbers are increased in some brain regions of Mecp2 mutant mice but decreased in others (Deng et al. 2010; Zhang et al. 2010). The ability of MEF2 overexpression to drive excitatory synapse elimination is impaired in mice lacking Fragile X mental retardation protein (FMRP) (Pfeiffer et al. 2010), suggesting a mechanistic link between the synaptic pathologies in Fragile X syndrome and the transcriptional pathways discussed here.