A7 Schizophrenia (dopaminergic and glutamatergic hypothesis)

Topic

The cortical circuit maintains normal activity through the balance between cortical inhibitory interneurons and the pyramidal neurons that constitute the circuit. In schizophrenia, a specific type of glutamate receptor loses function within the cortical circuit; this hypofunction reduces the excitation of cortical inhibitory interneurons, which in turn disinhibits the circuit's pyramidal neurons. This disinhibition of pyramidal neurons creates an excitation-inhibition imbalance within the cortical circuit—a type of imbalance previously identified in other cortical circuits—and this imbalance serves as the common starting point for the two dopaminergic alterations described by the model.

Stemming from this cortical circuit excitation-inhibition imbalance, one of the two dopaminergic alterations occurs in the mesolimbic dopaminergic pathway: this pathway becomes hyperactive, releasing more dopamine than usual, and this hyperactivity is associated with the positive symptoms of schizophrenia.

The other dopaminergic alteration arising from the same cortical circuit imbalance occurs in the mesocortical dopaminergic pathway: unlike the mesolimbic pathway, the mesocortical pathway becomes hypoactive, releasing less dopamine than usual, and this hypoactivity is associated with the negative and cognitive symptoms of schizophrenia.

Over time, the dopaminergic system—comprising both the mesolimbic and mesocortical pathways—becomes progressively sensitized to repeated stimuli: the more a stimulus is repeated, the more reactive the dopaminergic system becomes to it. This progressive sensitization of the dopaminergic system fosters a state of aberrant salience, in which neutral stimuli—normally lacking significance—acquire excessive motivational relevance for the individual.

According to this mechanism, the excessive motivational relevance acquired by neutral stimuli explains the formation of delusional ideas: the individual interprets actually neutral stimuli as significant, constructing a delusional explanation to justify that perceived relevance. Taken together, the cortical circuit—with its imbalance between excitation and inhibition—and the dopaminergic system—with its two pathways altered in opposite directions—constitute two components of the same process that, in schizophrenia, ultimately gives rise to negative and cognitive symptoms as well as positive symptoms and delusional ideas.

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