Each neuropsychiatric disorder that we discuss is associated with a distinct pattern of dendritic spine pathology, and mounting evidence implicates the altered structural plasticity of spines as a central disease mechanism in these disorders.Dendritic structural plasticityĪlthough multiple brain regions are likely to have a role in the development of neuropsychiatric disorders, the human neocortex has an important role in higher-order brain functions (such as cognition) that are dysfunctional in many neuropsychiatric disorders. In addition, epilepsy is often comorbid with intellectual disability and ASD, and individuals with epilepsy often present with various neuropsychiatric symptoms 10. Although epilepsy is typically classified as a neurological condition, we include it in this Review because it shares many genetic risk factors with ASD and intellectual disability 9.

We emphasize the integration of biological insights from large-scale genomic studies of idiopathic neuropsychiatric disorders of neurodevelopmental origin, including intellectual disability, epilepsy, autism spectrum disorder (ASD), schizophrenia and bipolar disorder. In this Review, we focus on the structural plasticity that occurs at postsynaptic sites, the dendrites and spines of excitatory neurons, which are atypical in several neuropsychiatric disorders and in which synaptic plasticity mechanisms have been extensively studied. Structural plasticity of circuits involves changes in both excitatory and inhibitory neurons and in both presynaptic and postsynaptic termini (reviewed in REF 2) however, genetic studies indicate that excitatory postsynaptic compartments may be particularly important in the aetiology of a wide range of neuropsychiatric disorders 5– 8. Remarkably, the pathways that are being uncovered intersect with mechanisms regulating the growth and structural plasticity of synapses, which may be important for understanding the nature of these disorders. Since the advent of genomic technologies, genetic risk factors for neuropsychiatric disorders are being identified at an unprecedented rate, providing a window into the molecular basis of disease. Neuropsychiatric disorders are a heterogeneous group of mental disorders that manifest psychiatric symptoms and demonstrable brain pathology and are thought to arise from disruptions of the synaptic circuits that subserve cognitive, social and emotional processing 4.

In particular, morphological changes in dendritic spines have been the focus of intense investigation owing to their proposed role in several neuropsychiatric disorders 3. The different sites of structural plasticity that work in concert to ensure precise brain wiring are therefore sensitive to dysregulation at multiple levels and on different timescales. Many neuronal subcompartments have been shown to change in response to activity these include dendritic arbors and spines, the axon initial segment and presynaptic boutons 2. The shaping of neuronal circuits occurs in sequential developmental phases and is refined by activity-dependent mechanisms and environmental cues 1. The highly specialized morphology of neurons provides the substrate to build the circuits that underlie human cognition and behaviour.

Dendrite structure