Mapping the Consequences of Impaired Synaptic Plasticity in Schizophrenia through Development: An Integrative Model for Diverse Clinical Features

Abstract

Schizophrenia is associated with alterations in sensory, motor, and cognitive functions that emerge before psychosis onset; identifying pathogenic processes that can account for this multi-faceted phenotype remains a challenge. Accumulating evidence suggests that synaptic plasticity is impaired in schizophrenia. Given the role of synaptic plasticity in learning, memory, and neural circuit maturation, impaired plasticity may underlie many features of the schizophrenia syndrome. Here, we summarize the neurobiology of synaptic plasticity, review evidence that plasticity is impaired in schizophrenia, and explore a framework in which impaired synaptic plasticity interacts with brain maturation to yield the emergence of sensory, motor, cognitive, and psychotic features at different times during development in schizophrenia. Key gaps in the literature and future directions for testing this framework are discussed.

Figure 1. The induction and expression of synaptic plasticity

During the induction of plasticity at excitatory synapses (A), glutamate activates postsynaptic AMPARs and NMDARs located in the postsynaptic density (PSD) of dendritic spines. AMPARs generate a fast excitatory postsynaptic response via Na+, while NMDARs initiate intracellular signaling cascades via Ca²⁺ that trigger local gene transcription; phosphorylation and synthesis of new PSD proteins; AMPAR trafficking to and from the membrane via actin dynamics; and reorganization of the actin cytoskeleton. When synaptic activity is sufficient to induce long-term potentiation (LTP), these processes lead to the insertion of reserve AMPARs into the postsynaptic membrane and the enlargement of the PSD and dendritic spine (B). Scaffold proteins such as PSD-95 stabilize the new AMPARs by trapping them in the membrane and reducing their lateral mobility. Changes in the size and shape of dendritic spines from baseline (C) scale with changes in synaptic efficacy and include (D): the elimination of spines (i); enlargement of spine heads and necks (ii); growth of new spines (iii); and the splitting of single PSDs and spines into two synapses (iv).

Figure 2. Synaptic Plasticity and Brain Maturation in the Healthy Brain and in Schizophrenia

(A) Developmental trajectories of excitatory synapses in representative cortical regions in the healthy brain. Within each region, synapses are initially overproduced and undergo a period of net synaptic pruning in which weak synapses are eliminated and adaptive synapses are strengthened. These synaptic refinements are thought to contribute to the maturation of finely tuned and functionally organized neural circuits mediating sensory, motor, and cognitive functions. (B) Hypothesized consequences of impaired synaptic plasticity across development in schizophrenia. Impaired synaptic plasticity in schizophrenia is predicted to lead to increased synaptic pruning and suboptimal fine-tuning of neural circuits. Regional differences in the trajectories of synaptic refinement and circuit maturation predict the timing of the emergence of sensory, motor, and higher cognitive signs in schizophrenia, with the magnitude of the impairments being positively associated with the age of their appearance. Dysregulated dopamine signaling emerges in adolescence as a downstream consequence of impaired cortical synaptic plasticity, and ultimately interacts with suboptimal neural tuning to yield psychotic symptoms in late adolescence or early adulthood.