Transcribing the connectome: roles for transcription factors and chromatin regulators in activity-dependent synapse development

Abstract

The wiring of synaptic connections in the developing mammalian brain is shaped by both intrinsic and extrinsic signals. One point where these regulatory pathways converge is via the sensory experience-dependent regulation of new gene transcription. Recent studies have elucidated a number of molecular mechanisms that allow nuclear transcription factors and chromatin regulatory proteins to encode aspects of specificity in experience-dependent synapse development. Here we review the evidence for the transcriptional mechanisms that sculpt activity-dependent aspects of synaptic connectivity during postnatal development and discuss how disruption of these processes is associated with aberrant brain development in autism and intellectual disability.

Keywords: activity-dependent synaptic plasticity; autism; chromatin; synapse development; transcription.

Fig. 1.

Mechanisms of specificity in the transcriptional regulation of synapses. A: calcium-response factor (CaRF) binds to Bdnf IV promoter and activates basal Bdnf transcription. It also inhibits activity-dependent Bdnf transcription via indirect activation of Grin3a expression, which encodes the NMDA receptor (NMDAR) subunit GluN3A. GluN3A inhibits NMDAR-induced Bdnf transcription without impairing the ability of L-type voltage-gated calcium channels to activate Bdnf transcription. B: Npas4 expression is induced rapidly by neuronal activity. Npas4 target genes promote GABAergic synapse formation at the soma while also inhibiting GABAergic synapse formation at the apical dendritic spines. C: neuronal activity induces MEF2-dependent gene transcription. FMRP traffics mRNAs from the nucleus to the synapses and represses local mRNA translation at the synapses until neuronal activation of mGluR5 receptors leads to target gene mRNA dissociation from FMRP. The ability of constitutively active MEF2-VP16 to drive synapse elimination is blocked in FMRP-knockout neurons, suggesting that these 2 pathways converge to locally regulate synapse pruning.

Fig. 2.

Domain organization and posttranslational regulatory modifications of MEF2 family members in neurons. MEF2A, -C, and -D proteins all contain NH₂-terminal MADS and MEF2 domains (gray and brown), which mediate DNA binding and dimerization, and a conserved transactivation domain (TAD, green). α, β, and γ indicate alternatively spliced exons. In neurons the MEF2s predominantly contain the α₁ splice variant and are β+. The γ-domain is constitutively present in MEF2A and MEF2D but alternatively spliced in MEF2C. Figure shows posttranslational modifications (P, phosphorylation; SUMO, sumoylation; Ac, Acetylation) and their residue locations in human MEF2A. Whether the modifications function to enhance or repress MEF2 activity is shown above the diagram.

Fig. 3.

Chromatin regulatory factors in synapse development. A: neuronal-specific accumulation of methyl-CpH leads to a distinct MeCP2-regulated gene program in mature neurons. Top: during brain development methyl-CpH levels increase and accumulate selectively in mature neurons, whereas methyl-CpG levels are constant across development in both neurons and glia. Bottom: because MeCP2 binds to both methyl-CpG and methyl-CpH, the distinct high level of methyl-CpH in mature neurons leads to a neuron-specific developmental effect on MeCP2 regulated gene transcription. Diagrams are based on the data in Lister et al. (2013) and Chen et al. (2015). B: tissue-specific BAF subunits interact with distinct transcription factors or transcriptional coactivators, resulting in activation of different gene programs during neural development. BAF complexes regulate a group of synaptic genes and mediate synapse formation and maturation. In activated neurons, BAF complexes regulate Arc and Grin2b expression by interacting with CBP. BAF complexes also interact with MEF2C and are required for MEF2C-mediated synapse elimination. C: NuRD controls the timing of gene expression by turning genes off both on a developmental timescale and in response to transient neuronal activity. During cerebellar development, NuRD turns off genes that suppress presynaptic differentiation by histone deacetylation and inactivates neuronal activity-dependent gene transcription by replacing H2A with H2A.Z.