Activity-dependent neuronal signalling and autism spectrum disorder

Abstract

Neuronal activity induces the post-translational modification of synaptic molecules, promotes localized protein synthesis within dendrites and activates gene transcription, thereby regulating synaptic function and allowing neuronal circuits to respond dynamically to experience. Evidence indicates that many of the genes that are mutated in autism spectrum disorder are crucial components of the activity-dependent signalling networks that regulate synapse development and plasticity. Dysregulation of activity-dependent signalling pathways in neurons may, therefore, have a key role in the aetiology of autism spectrum disorder.

Figure 1. Regulation of synaptic development and function by neuronal activity

Cell adhesion molecules and components of the postsynaptic density organize and regulate the formation of excitatory synapses on dendritic spines and can stimulate activity-dependent signalling networks within the postsynaptic neuron. At the synapse, the excitatory neurotransmitter glutamate can bind several glutamate receptors — NMDA receptor (NMDAR), AMPA receptor (AMPAR) and mGlu receptor (mGluR). Signalling from stimulated mGluR regulates mRNA translation, which is required for long-lasting forms of synaptic plasticity. Modification and cell-surface expression of AMPA receptors underlies many aspects of synaptic plasticity. Stimulated NMDA receptors flux calcium, inducing calcium-dependent signalling networks at the synapse that regulate AMPA receptor function and actin reorganization. In addition, calcium influx through NMDA receptor and L-type voltage-sensitive calcium channels (L-VSCC) triggers calcium-dependent signalling to the nucleus, leading to the modification of transcriptional regulators and resulting in the induction of activity-dependent gene expression. Genes induced by neuronal activity — including Bdnf, Arc, and Ube3A — function to regulate synapse formation, maturation, elimination and plasticity. P, phosphorylation.

Figure 2. Neuronal activity regulates mRNA translation and synaptic plasticity

At the excitatory synapse, the cell adhesion molecules neurexin and neuroligin and structural proteins in the postsynaptic density, including Shank proteins, regulate, and are regulated by, neuronal activity-dependent signalling networks. The excitatory neurotransmitter glutamate binds NMDA receptors (NMDAR), AMPA receptors (AMPAR) and mGlu receptors (mGluRs). AMPA receptors mediate the fast excitatory neurotransmission. UBE3A degrades Arc, which regulates trafficking of AMPA receptors. During plasticity, activation of NMDA receptors triggers calcium-dependent signalling at the synapse, stimulating CaMKII and modifying AMPA receptor function and actin reorganization. Activation of mGluR triggers several signalling cascades, including the PI(3)K–AKT–mTOR pathway, the Ras–MAPK pathway, and PLC to regulate mRNA translation. FMRP inhibits mRNA translation, and mGluR signalling can regulate FMRP activity. Growth factors, including BDNF, whose expression is induced by neuronal activity, bind receptor tyrosine kinases (including TrkB) that activate multiple signalling pathways, including the PI(3)K–AKT pathway. The PI(3)K–AKT pathway when activated leads to phosphorylation of the TSC1–TSC2 complex to control mTOR activity. Mutations in neurexins, neuroligins, SHANK, GKAP, UBE3A, FMRP and TSC1–TSC2 are associated with ASD.

Figure 3. Activity-dependent gene expression and ASD

Activation of NMDA receptors and L-type voltage-sensitive calcium channels (L-VSCC) trigger calcium influx and induction of calcium-dependent signalling molecules, including CaMKK that activates the kinases CaMKII and CaMKIV, calcium-sensitive adenylyl cyclases (AC) that activate PKA, and the calcium dependent phosphatase calcineurin. In addition, the RAS–ERK–RSK/MSK pathway is activated upon stimulation of L-VSCC. These signalling cascades phosphorylate or dephosphorylate transcriptional regulators in the nucleus, leading to the expression of transcription factors (shown as c-Fos and NPAS4). These transcription factors contribute to the regulation of activity-dependent gene transcription and to the expression of effectors that function to modify synapses (shown as BDNF, Arc and Ube3A). In addition, changes in chromatin modifications (including histone acetylation), and the phosphorylation of chromatin-associated proteins (for example, MECP2) may modulate activity-dependent gene transcription. Mutations of proteins involved in activity-dependent gene expression are associated with some forms of ASD including L-VSCC in Timothy syndrome, RSK2 in Coffin-Lowry, CBP in Rubenstein-Taybi, Ube3A in Angelman syndrome and MeCP2 in Rett syndrome. Ac, acetylation; CaRF, calcium response factor; Me, methylation; P, phosphorylation

Figure 4. BDNF regulates mRNA translation

Neuronal activity potently induces expression of the neurotrophic factor BDNF. BDNF binds the receptor TrkB, a receptor tyrosine kinase, triggering several signalling cascades, including the PI(3)K–AKT and Ras–MAPK pathways. PI(3)K is a lipid phosphatase, converting PtdIns(4,5)P₂ to PtdIns(3,4,5)P₃, which can be reversed with the phosphatase PTEN. PDK1 together with PtdIns(3,4,5)P₃ activates AKT, which inhibits TSC1–TSC2. TSC1–TSC2 serves as a GAP for the GTPase Rheb, promoting the conversion of active GTP bound Rheb to the inactive GDP bound form. Rheb-GTP activates mTOR to induce mRNA translation. PTEN and TSC1–TSC2 are associated with ASD, as are mutations in Ras, Raf, MEK1–MEK2.