Dendritic spine pathology in neuropsychiatric disorders

Abstract

Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets. Here we discuss recent neuropathological, genetic, molecular and animal model studies that implicate structural alterations at spiny synapses in the pathogenesis of major neurological disorders, focusing on ASD, schizophrenia and Alzheimer's disease as representatives of these categories across different ages of onset. We stress the importance of reverse translation, collaborative and multidisciplinary approaches, and the study of the spatio-temporal roles of disease molecules in the context of synaptic regulatory pathways and neuronal circuits that underlie disease endophenotypes.

Figure 1

Putative lifetime trajectory of dendritic spine number in the in a normal subject (black), in ASD (pink), in schizophrenia (SZ, green) and in Alzheimer’s disease (AD) (blue). Bars across the top indicate the period of emergence of symptoms and diagnosis. In normal subjects, spine numbers increase before and after birth; spines are selectively eliminated during childhood and adolescence to adult levels. In ASD, exaggerated spine formation or incomplete pruning may occur in childhood leading to increased spine numbers. In schizophrenia, exaggerated spine pruning during late childhood or adolescence may lead to the emergence of symptoms during these periods. In Alzheimer’s disease, spines are rapidly lost in late adulthood, suggesting perturbed spine maintenance mechanisms that may underlie cognitive decline.

Figure 2

Model of molecular mechanisms of spine pathology in ASD. Proteins with genetic associations with ASD and comorbid disorders participate in pathways that regulate spine morphogenesis. Their disruption may alter spine dynamics and stability, leading to an increase in spine density and increased connectivity with nearby axons (blue lines) during early childhood.

Figure 3

Model of molecular mechanisms contributing to spine dysfunction in schizophrenia. Molecules genetically or neuropathologically implicated in schizophrenia interact with regulators of spine plasticity and maintenance. Their disruption may lead to exaggerated spine loss and loss of connectivity with axons (blue lines) in late adolescence or early adulthood.

Figure 4

Model of molecular mechanisms involved in spine pathology in Alzheimer’s disease. Aβ oligomers disrupt synaptic plasticity mechanisms and induce spine dysgenesis, likely by interfering with NMDAR-dependent regulation of the spine cytoskeleton, causing synapse loss and decreased connectivity with nearby axons (blue lines) later in life.