No abstract

Early models for the etiology of schizophrenia focused on dopamine neurotransmission because of the powerful antipsychotic action of dopamine antagonists. Nevertheless, recent evidence increasingly supports a primarily glutamatergic dysfunction in this condition, where dopaminergic disbalance is a secondary effect. A current model for the pathophysiology of schizophrenia involves a dysfunctional mechanism by which the NMDA receptor (NMDAR) hypofunction leads to a dysregulation of GABA fast-spiking interneurons, consequently disinhibiting pyramidal glutamatergic output and disturbing the signal-to-noise ratio. This mechanism might explain better than other models some cognitive deficits observed in this disease, as well as the dopaminergic alterations and therapeutic effect of anti-psychotics. Although the modulation of glutamate activity has, in principle, great therapeutic potential, a side effect of NMDAR overactivation is neurotoxicity, which accelerates neuropathological alterations in this illness. We propose that metabotropic glutamate receptors can have a modulatory effect over the NMDAR and regulate excitotoxity mechanisms. Therefore, in our view metabotropic glutamate receptors constitute a highly promising target for future drug treatment in this disease.

Objective: The ability to perceive the motion of biological objects, such as faces, is a critical component of daily function and correlates with the ability to successfully navigate social situations (“social cognition”). Deficits in motion perception in schizophrenia were first demonstrated ~20 years ago but remain understudied, especially within the early, potentially prodromal, stages of the illness. The authors examined the neural bases of visual sensory-processing impairments, including motion, in schizophrenia and attenuated psychosis (clinical high risk) patients relative to age-matched controls. Methods: Electrophysiological recordings during stimulus and motion processing were analyzed using oscillatory (“time frequency”) approaches that differentiated motion-onset evoked activity from stimulusonset sensory-evoked responses. These were compared to functional MRI measures of motion processing. Results: Significant deficits in motion processing were observed across the schizophrenia and attenuated psychosis populations and these deficits predicted impairments in both face-emotion recognition and cognitive function. In contrast to motion, sensory-evoked stimulus-onset responses were intact in attenuated psychosis individuals and, further, the relative deficit in motion-versus stimulus-onset responses predicted transition to schizophrenia. In schizophrenia patients, motion detection deficits mapped to impaired activation of motion-sensitive visual cortex (area MT+) during fMRI. Additional visual impairments in schizophrenia patients, not present in individuals with attenuated psychosis, implicated other visual regions, including the middle occipital gyrus and the pulvinar thalamic nucleus. Conclusions: The present study emphasizes the importance of sensory-level visual dysfunction in the etiology and personal experience of individuals with schizophrenia, and demonstrates that motion processing deficits may predate illness onset and contribute to impaired function even in clinical high risk, attenuated psychosis patients.