The synaptic hypothesis of schizophrenia version III: a master mechanism

Abstract

The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there has been a step-change in the evidence available, and some tenets of earlier versions are not supported by recent findings. Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. We then consider the mechanism that could underlie synaptic changes and update the hypothesis. Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss. Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. Based on this evidence, we propose version III of the synaptic hypothesis. This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. It accounts for the typical onset of schizophrenia in adolescence/early adulthood, its major risk factors, and symptoms, and identifies potential synaptic, microglial and immune targets for treatment.

Fig. 1. Citations per year, from 1982 to 2021, when searching for topic: (schizophrenia) and topic: (synap*) in Web of Science™.

The first arrow indicates the year Feinberg’s hypothesis was published. The second arrow indicates the year Keshavan et al.’s hypothesis was published.

Fig. 2. The normal trajectory of synaptic density over age, reflecting an initial phase of net synaptic production, followed by net synaptic elimination from late childhood/adolescence into early adulthood, and then relatively balanced synaptic elimination and production in middle age.

Adapted from post-mortem data reported by Petanjek et al. for basal dendritic spine density of pyramidal cells from layer IIIc [34].

Fig. 3. Mechanism for glia-mediated synaptic pruning via the classical complement signalling cascade.

Complement component C1q interacting with binding partners triggers cleavage of the complement components C2 and C4, thereby promoting the generation of activated C3. Activated C3 induces synaptic phagocytosis by microglia. Other complement signalling pathways can also trigger phagocytosis.

Fig. 4. Showing the mechanism potentially leading to aberrant synaptic pruning in schizophrenia.

Left: potential model of glia-mediated elimination of synapses in schizophrenia. This could affect glutamatergic synapses, including dendritic spines and collaterals that synapse onto inhibitory interneurons, as well as inhibitory synapses onto pyramidal neurons. Right: loss of synapses on pyramidal neurons and inhibitory interneurons, which could disrupt pyramidal neuron function and lead to negative and cognitive symptoms.

Fig. 5. The synaptic hypothesis of schizophrenia version III.

This is a multi-hit model in which genetic variants increase the vulnerability of synapses to elimination, and subsequent environmental risk factors such as stress, then induce aberrant glial-mediated pruning. Aberrant synaptic pruning leads to cortical excitation-inhibition imbalance, resulting in cognitive impairment and negative symptoms, and dysregulated projections to the striatum and midbrain. This leads to dopaminergic neuron disinhibition, and impairments in predictive learning and processing of sensory stimuli, causing psychotic symptoms. The stress of psychosis feeds back on this system to lead to further aberrant pruning.