Resolving the Synaptic versus Developmental Dichotomy of Autism Risk Genes

Abstract

Genes that are mutated in Autism Spectrum Disorders (ASD) can be classified broadly as either synaptic or developmental. But what if this is a false distinction? A recent spate of publications has provided evidence for developmental mechanisms that rely on neural activity for proper cortical development. Conversely, a growing body of evidence indicates a role for developmental mechanisms, particularly chromatin remodeling, during learning or in response to neural activity. Here, we review these recent publications and propose a model in which genes that confer ASD risk operate in signal transduction networks critical for both cortical development and synaptic homeostasis.

Keywords: E/I balance; autism; chromatin; cortical development; genetics; genomics; neural activity; neuron migration; precision medicine; sensory integration; signal transduction; synapse.

Figure 1:. Glutamatergic neurotransmission is required for cortical migration.

A) Cortical excitatory neurons arise from neural progenitor cells (NPCs) and exit the ventricular zone as migrating multipolar neurons. As they cross the subplate, they change into a bipolar morphology for their final migration into the cortical plate. B) This multipolar-to-bipolar transition is dependent on NMDAR- and PSD95-dependent excitatory synapses forming between subplate neurons and migrating multipolar cells. C) In Fragile X, and potentially other models of ASD, disrupted glutamatergic signal transduction pathways lead to an accumulation of multipolar neurons below the subplate, and delayed cortical migration. D) In the early postnatal period, BrdU or electroporation-labeling studies in mice revealed incomplete migration compared to age-matched controls (E14: embryonic day 14). E) However, by adulthood, these differences normalize, leaving no cytoarchitectural trace of developmental delay.

Figure 2:. Glutamatergic neurotransmission is required for GABA neuron survival.

A) GABAergic neurons migrate tangentially, from their origin in the medial ganglionic eminence to their final locations in the cortex, arriving in the early postnatal period (illustration timing refers to mice; P5–8: postnatal days 5 to 8). B) Upon arrival, GABAergic neurons must form excitatory glutamatergic synapses with local cortical neurons. Transmission through these synapses promotes survival in a PTEN-dependent manner. C) If the timing of excitatory neuron migration is disrupted by an ASD-linked risk factor, local cortical neurons may not have yet reached their final position, or they may be too immature to form functional synapses. D) If local pyramidal cells are unable to form synapses with GABAergic neurons, PTEN activity increases, leading to reduced mTOR pathway activation and increased apoptosis of GABAergic neurons.

Figure 3,. Key Figure: ASD-linked ‘synaptic’ and ‘developmental’ proteins involved in synaptic homeostasis.

This cartoon view of a neuron, with an expanded synaptic spine to show proteins, illustrates some of the many ASD-linked proteins involved in synaptic homeostasis and plasticity. At the synapse, neurotransmitter receptors, tethered in place by synaptic adhesion molecules and intracellular scaffolding proteins, transmit molecular cues to kinases and other effectors. Signal transduction cascades carry these signals to the nucleus, where histone modifying enzymes and helicases regulate chromatin accessibility. RNA is then spliced and further processed into export granules, which are transported into the dendrite for local protein synthesis. Disruption of any protein in this complex and spatially distributed process could alter the overall homeostatic balance of the synapse. ASD-linked genes are involved at each step. Gene/protein acronyms, ordered according to the two “key” insets: DLGs: Disks large homologs; AMPAR: AMPA-selective glutamate receptor; NMDAR: N-methyl-D-aspartate receptor; mGluRs: metabotropic glutamate receptors; CaV42.1: Voltage-gated calcium channel 2.1; Shanks: SH3 and multiple ankyrin repeat domains proteins; SynGAP: Synaptic Ras GTPase-activating protein; CaMKII: Calcium/calmodulin-dependent protein kinase type II; PI3K: Phosphatidylinositol 4,5-bisphosphate 3-kinase; PTEN: Phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase; FMR1: Fragile X mental retardation protein 1; EIF4: Eukaryotic translation initiation factor 4; CHD8: Chromodomain-helicase-DNA-binding protein 8; HDACs: Histone deacetylases; DNAMT: DNA methyltransferase.