Retinal Origins of Aberrant Salience in Schizophrenia: The Perceptual Theory

AI Summary

Perceptual Theory proposes unstable retinal dopamine signalling initiates schizophrenia in a subset, positioning the visual periphery upstream of cortical dysfunction.
Retinal dopamine acts as a master gain controller via D1 and D2 receptors, altering receptive fields and spatial frequency processing to produce noisy sensory input.
Noisy retinal signals cascade through thalamocortical circuits, disrupting predictive salience, provoking synaptic sprouting and complement-mediated hyperpruning, explaining symptom timing and heterogeneity.

AI Summary

However, the epidemiological observation that congenital cortical blindness appears to confer protection against schizophrenia, while peripheral blindness, regardless of its developmental timing, does not, indicates that visual input itself may play a more fundamental role in disease pathogenesis.

Here we propose the Perceptual Theory of Schizophrenia (PerTh), a framework positing that instability in retinal dopamine signaling acts as an initiating mechanism in a subset of individuals.

We propose that schizophrenia-associated genetic liabilities, encompassing dopaminergic, GABAergic (gamma-aminobutyric acidergic), neuroimmune, and other risk factors, converge on retinal dopamine homeostasis, producing chronically unstable signals that corrupt the sensory foundation upon which predictive models of reality are built.

Basic summary

Biol Psychiatry Glob Open Sci. 2026 Jun 4;6(5):100764. doi: 10.1016/j.bpsgos.2026.100764. eCollection 2026 Sep.

ABSTRACT

In schizophrenia research, visual processing abnormalities have traditionally been viewed as downstream consequences of cortical dysfunction. However, the epidemiological observation that congenital cortical blindness appears to confer protection against schizophrenia, while peripheral blindness, regardless of its developmental timing, does not, indicates that visual input itself may play a more fundamental role in disease pathogenesis. Here we propose the Perceptual Theory of Schizophrenia (PerTh), a framework positing that instability in retinal dopamine signaling acts as an initiating mechanism in a subset of individuals. Retinal dopamine functions as a master gain controller, modulating receptive field properties and spatial frequency processing through D₁ and D₂ receptor-mediated mechanisms. We propose that schizophrenia-associated genetic liabilities, encompassing dopaminergic, GABAergic (gamma-aminobutyric acidergic), neuroimmune, and other risk factors, converge on retinal dopamine homeostasis, producing chronically unstable signals that corrupt the sensory foundation upon which predictive models of reality are built. This noisy input cascades through thalamocortical pathways, disrupting physical and cognitive salience formation; driving compensatory synaptic sprouting; and ultimately rendering diffuse, weak connections vulnerable to complement-mediated hyperpruning during adolescence. The framework integrates retinal electrophysiology, Bayesian predictive processing, and neurodevelopmental pruning mechanisms to explain symptom emergence timing, the predominance of auditory over visual hallucinations, and phenotypic heterogeneity. PerTh does not seek to replace existing dopaminergic, glutamatergic, neuroimmune, or neurodevelopmental models but instead complements them by identifying a potential upstream contribution originating in the visual periphery. This perspective generates testable predictions and points to novel research directions targeting retinal function in psychosis.

PMID:42471972 | PMC:PMC13380484 | DOI:10.1016/j.bpsgos.2026.100764

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