The Molecular Machinery of Synaptic Plasticity and Its Potential Role in the Aetiology of Schizophrenia.

Altered glutamatergic and dopaminergic transmission in regions including cortex and hippocampus is thought to contribute to schizophrenia symptoms. The prominent role of glutamate (particularly via NMDA receptors) and dopamine (particularly via D2 receptors) in synaptic plasticity, and the impairment of plasticity-associated cognitive function in the condition, has suggested that schizophrenia may be viewed as a disorder of synaptic plasticity. This is encouraging, as regards developing improved treatments, as plasticity by its nature is dynamic and malleable. However, there are many distinguishable forms of synaptic plasticity, and it is not immediately obvious whether all forms are affected, and throughout the brain, or whether specific forms of plasticity are compromised, and only in certain brain regions. Here, I describe the molecules mediating various forms of plasticity, and collate the electrophysiological, imaging, pathological, genetic and biochemical evidence to address their possible dysfunction in schizophrenia. The overall picture is consistent with suboptimal function of all forms of plasticity, in circuitry centred on prefrontal cortex and thalamus. Many of the neurobiological changes characteristic of schizophrenia (reduced metabolic activity, GABAergic interneuron gene expression and dendritic spine density, in circuitry centred on prefrontal cortex) can be viewed as consequences of compromised plasticity rather than fundamental aetiological factors. Of hundreds of genes potentially contributing to genetic risk, more than 60 are directly implicated in plasticity processes, comprising receptors, voltage-sensitive Ca