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.

Inability to activate Rac1-dependent forgetting contributes to behavioral inflexibility in mutants of multiple autism-risk genes

“…Are there causal paths that can determine the onset of autism? Answering these questions is difficult because the disorder is multifactorial in nature with multiple genetic variants and environmental factors contributing to the core symptoms (10)(11)(12)(13). To face this challenge, extensive efforts have been made to identify the targeting and functional convergence of the autism-risk genes, such as those involved in translation regulation (14)(15)(16) and long-range connectivity among different brain regions (17)(18)(19).…”

A Fragile Balance: Dendritic Spines, Learning, and Memory

“…The story that has emerged highlights an essential aspect of neurophysiology that may be relatively underappreciated in clinical settings: namely, the importance of dendritic spines and the role they play in neural plasticity (4). …”

“…The existence of the dendritic spine first came to light thanks to 19th-century neuroscientist Santiago Ramón y Cajal, who observed that certain dendrites were studded with protrusions that resembled “thorns or short spines” (4). We now know that spines only exist on certain types of neurons (including pyramidal neurons in the cortex and Purkinje cells in the cerebellum) (5).…”

“…Spines begin to grow when the dendrite plasma membrane starts forming tentacle-like projections called filopodia (4). These protrusions create synapses with nearby axons and eventually mature into spines.…”

“…These protrusions create synapses with nearby axons and eventually mature into spines. Ultimately, about half of these synapses will be pruned during childhood and adolescence (4). …”