Dendritic spine dysgenesis in autism related disorders

Abstract

The activity-dependent structural and functional plasticity of dendritic spines has led to the long-standing belief that these neuronal compartments are the subcellular sites of learning and memory. Of relevance to human health, central neurons in several neuropsychiatric illnesses, including autism related disorders, have atypical numbers and morphologies of dendritic spines. These so-called dendritic spine dysgeneses found in individuals with autism related disorders are consistently replicated in experimental mouse models. Dendritic spine dysgenesis reflects the underlying synaptopathology that drives clinically relevant behavioral deficits in experimental mouse models, providing a platform for testing new therapeutic approaches. By examining molecular signaling pathways, synaptic deficits, and spine dysgenesis in experimental mouse models of autism related disorders we find strong evidence for mTOR to be a critical point of convergence and promising therapeutic target.

Keywords: Fragile X; Intellectual disability; MeCP2; Rett syndrome; TrkB; mGluR; mTOR.

Figure 1. Characterization of dendritic spines in autism related disorders

Numerical density of dendritic spines during neurodevelopmental stages, and morphologies of mature spines in different ARDs. In typical subjects (grey shading), spines and synapses are formed during early development with the excess or weaker connections being selectively pruned in adolescence, after which spines are maintained during adulthood. Morphological types of spines include thin, mushroom, and stubby, filopodia-like spines are uncommon in the mature brain. Tuberous Sclerosis (purple) has a lower density during spinogenesis, is within typical levels in the pruning stage, and higher densities during maturity with normal morphology. Fragile Xsyndrome (blue) has higher densities until the maintenance stage has been reached, when the density lowers to typical levels and have spines that are morphologically more immature, including a higher proportion of thin and filopodia-like spines. Rett syndrome (green) has a lower density until the maintenance phase with a lower proportion of mushroom spines. There is a lack of density data in Angelman syndrome (red) for both the spinogenesis and pruning stages, but mouse models have lowered densities in the maintenance phase with more variable spine morphology. Down syndrome (brown) has lower densities after the spinogenesis phase with remaining spines having larger heads and longer necks.

Figure 2. Pathways involved in the translational regulation of “LTD proteins”

ARDs share molecular pathologies affecting a common signaling pathway involved in activity-dependent protein synthesis in distal dendrites near spine synapses. The Ras/ERK and PI3K/mTOR signaling pathways couple synaptic activation of mGluR and the BDNF TrkB receptors to protein translation that is essential to the maintenance of LTD. Mutations in several regulators of these pathways, including the genes encoding the proteins TSC1/2, FMRP, DSCR1, UBE3A, and PTEN are responsible for ARDs. Loss-of-function mutations in the gene encoding the nuclear protein MeCP2, which causes RTT, result in lower levels of mGluR and BDNF, lowering the activation of those signaling pathways in response to glutamatergic synaptic activity and activity-dependent BDNF release. While mTOR is typically an activator of protein translation through 4E-BP and S6K, pathological increases in mTOR levels repress translation of LTD-specific proteins, though the exact mechanism(s) is unknown. Selective inhibition of mTOR with rapamycin alleviates autism-related deficits in FXS and TS, providing evidence that this pathway is causal in the pathological mechanisms leading to autism. Abbreviations: Glu: glutamate; Ras: rat sarcoma proto-oncogenic G-protein; MEK: MAPK kinase; ERK: extracellular signal-related kinase; Rheb: RAS homolog enriched in brain; Mnk: MAP kinases phosphorylate; elF4E: Eukaryotic initiation factor 4E; 4E-BP: eukaryotic translation initiation factor 4E binding protein; S6: ribosomal protein S6; S6K: S6 kinase; 40S: eukaryotic small ribosomal subunit; PI3K: phosphoinositide 3-kinase; PDK: phosphoinositide-dependent kinase; P: phosphate.