Adolescent onset of cortical disinhibition in schizophrenia: insights from animal models

Abstract

Schizophrenia and related mental disorders are common and devastating conditions for which we have a limited understanding of their origin and mechanisms. Although this apparent lack of progress despite vast research efforts could be due to difficulties in reproducing the disease in animals, animal work is now providing important insight onto possible pathophysiological changes in the brain. Postmortem studies of human brains have provided data indicating altered local inhibitory circuits in the cerebral cortex in schizophrenia and different developmental, pharmacological, and genetic animal models converge in revealing deficits in cortical interneuron function that can be associated with neurophysiological and behavioral alterations resembling aspects of the disease. Schizophrenia pathophysiology has a complex developmental trajectory because overt symptoms become evident during late adolescence despite earlier events contributing to the disease. The late incidence of schizophrenia can be explained by the protracted maturation of brain circuits implicated in the disease, particularly during adolescence. Excitatory and inhibitory processes in cortical circuits are tightly modulated by dopamine (DA), and many aspects of DA function in cortical regions acquire their adult profile during adolescence. This maturation fails to occur or is abnormal in several different rodent models of schizophrenia, yielding a number of functional and behavioral deficits relevant to the disease. Thus, periadolescent changes in cortical inhibitory circuits are a critical developmental stage likely implicated in the transition to schizophrenia. These observations provide the foundation for novel research-based therapeutic approaches and perhaps will even lead to ways to prevent the progression of the disease in predisposed subjects.

Fig. 1.

Periadolescent maturation of the dopamine (DA) modulation of prefrontal cortex (PFC) circuits. Top: schematic representation of a juvenile circuit; left: DA receptor effects in pyramidal neurons (D₁ receptors increase cell excitability and glutamate responses; D₂ receptors decrease cell excitability and glutamate responses) and gamma amino butyric acid (GABA) interneurons (D₁ agonists enhance cell excitability and D₂ agonists have a weak inhibitory effect). Right: levels of activity in a hypothetical network of PFC pyramidal cells are displayed with darker being higher. In this illustration of a juvenile network, the more strongly activated neuron (arrow) stands out from the rest. Middle: similar schematic representation of an adult PFC circuit. In the adult, D₁ receptors increase NMDA responses in pyramidal neurons more effectively and D₂ receptors increase GABA interneuron activity. The result is a higher contrast between strongly activated and weakly activated units (right). Bottom: In a circuit in which interneurons fail to be properly activated by DA, such as what is observed in animal models of schizophrenia, the contrast between strongly and weakly activated units is blurred, and there may be even units that are improperly enhanced (downward arrow), thereby the encoding of goals and decision making by the PFC becomes inefficient.

Fig. 2.

Cartoon a cortical interneuron and a representative glutamatergic afferent indicating where vulnerability factors can affect interneuron function during development, and possible events occurring in animal models that ultimately yield disinhibited cortical circuits. There may be many ways to alter interneuron function that yield disinhibited cortical circuits. Some manipulations affect NMDA receptor function in GABAergic interneurons, and these could be driven by NMDA antagonists, reduced inputs, trophic factors, etc. Reduced NMDA activation in this cell population induces cytokine expression and redox alterations, and in the end, the reduced activity of these neurons yields lower levels of parvalbumin. Genetic risk factors may contribute to this scenario both at the presynaptic and postsynaptic level.