The prospect of an intrinsic antipsychotic defense within the human brain

Abstract

Converging evidence links schizophrenia risk to synaptic dysfunction due to genetic variants. Synaptic dysplasticity in at-risk individuals lead to excessive synapse elimination, impacting brain connectivity. MRI studies highlight initial hyperconnectivity followed by later hypoconnectivity, impacting information transmission. Imbalance between Hebbian and homeostatic plasticity likely causes this shift. Highly connected hub regions of the brain experience synapse reduction, causing what we call as ‘global retuning’. Such post-psychotic changes aid resolution of active symptoms but lead to cognitive and motivational deficits. Antipsychotics may restore connectivity but worsen cognitive symptoms. In this framework, we present schizophrenia as an illness with disrupted ‘topological homeostasis’ due to synaptic dysplasticity. Our framework leaves room for an intrinsic, albeit inefficient, antipsychotic defense process that aids in adaptation. Studying successful adaptation in animal models and recovered individuals is crucial to design avant-garde interventions for schizophrenia.