Unmasking Schizophrenia: Synaptic Pruning in Adolescence Reveals a Latent Physiological Vulnerability in Prefrontal Recurrent Networks

Abstract

Theories of the pathophysiology in schizophrenia are converging on the synapse. This special issue of Biological Psychiatry collects papers from leading researchers that suggest a hypothesis that multiple factors spanning many levels lead to synaptic dysfunction in recurrent circuits in the prefrontal cortex (PFC). The hypothesis (Figure 1) suggests that the defect within the PFC is established during early development but remains latent through childhood. Pruning of excitatory synapses during adolescence, resulting in lower synaptic density in persons with schizophrenia, triggers the emergence of symptoms. The lower synaptic density results in deficits in cognitive processes, including working memory, because overpruned neural circuits cannot support the relevant computations ( 1 Averbeck B.B. Pruning recurrent neural networks replicates adolescent changes in working memory and reinforcement learning. Proc Natl Acad Sci U S A. 2022; 119e2121331119 Crossref Scopus (0) Google Scholar ). Additionally, excessive prefrontal pruning leads to striatal hyperdopaminergia through increased activation of midbrain dopamine neurons by prefrontal input. The decreased synaptic density following adolescent pruning could be due to genetic or epigenetic effects that lead to an inability to build stable synapses or excessive pruning of established synapses. The excessive pruning could follow from overactive pruning mechanisms or from decreased excitatory synaptic activity due to synaptic changes local to the PFC or prolonged decreases in thalamic input across development. All of these factors may converge to alter spike timing dynamics in prefrontal recurrent circuits in adolescence, reducing synchronous neural activity and accelerating synaptic disconnection via activity-dependent mechanisms ( 2 Zick J.L. Crowe D.A. Blackman R.K. Schultz K. Bergstrand D.W. DeNicola A.L. et al. Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits. Curr Biol. 2022; 32: 14-25.e4 Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar ). Further, synaptic pruning is mediated by components of the immune system, and in utero immune challenge may affect adolescent pruning. Decreased synaptic activity can also lead to increased pruning as pruning removes weak synapses. Thus, multiple effects converging on the synapse could lead to a PFC with fewer excitatory synaptic connections, and this decreased recurrent connectivity could lead to cognitive deficits and increased striatal dopamine and psychosis.