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Background Molecular imaging with Positron Emission Tomography (PET) has the unique capability of examining molecules in the brains of human subjects in real time. This has been well exploited in the study of dopaminergic transmission in schizophrenia. The results have on one hand confirmed some predictions, and on the other hand they have brought up unexpected findings, that have the potential to affect drug development in a major way. Methods PET studies of dopamine release, synthesis, storage, receptors and transporters across labs and different experiments will be reviewed to extract findings that differ from preconceived notions. These have the capability of re-focusing drug development based on new evidence. Results Expected findings that PET studies have confirmed are those of striatal dopaminergic excess, measured as enhanced presynaptic release capacity and presynaptic enzymatic synthesis capacity. Also expected was hypodopaminergic transmission in the dorso-lateral prefrontal cortex. The unexpected findings from PET have been as follows: 1) the striatal excess is most predominant in the associative striatum, rather than the limbic striatum. 2) hypodopaminergia is generalized to all extrastriatal areas of the brain These observations of opposite presynaptic dopaminergic dysfunction between striatal and extrastriatal regions suggest that the striatal excess may not be driven by activity levels of midbrain DA cells but may result from abnormal striatal local regulation of presynaptic DA release, affecting specifically the associative striatum, region which shows largest magnitude of excess DA. Furthermore alterations in dopaminergic signaling in opposing directions may have a dual effect on learning across functional domains by weakening learning from salient or relevant signals and reinforcing stimulus independent signals, thus explaining different symptom domains. Discussion More work is needed to understand the cellular mechanisms of dopaminergic dysfunction in schizophrenia. The evidence presented here, while limited, highlights the challenges of drug development in the absence of real in vivo information from patients, and the need for multidisciplinary cross talk to address these challenges.

Background In schizophrenia (SCH), proton MRS studies of the medial prefrontal cortex (MPFC) show elevated glutamine (Gln) or the combination of Glu and Gln (Glx) in unmedicated patients. Studies in healthy human subjects demonstrate ketamine-induced acute increases in MPFC Glu or Gln. Together, these findings raise the question of potential disturbances in excitation-inhibition balance in the illness, possibly arising from NMDA receptor deficits in GABAergic interneurons. We investigated these questions following acute ketamine administration by using repeated 15-minute MRS acquisitions of Glx and GABA with simultaneous EEG and comparing the results with the same modalities acquired in SCH. Methods We enrolled 11 healthy volunteers (age 18–55) who were given a constant i.v. infusion of ketamine 0.5 mg/kg over 40 min during a combined EEG and 1H MRS study. Glx and GABA were acquired in the pregenual MPFC using a 3T GE system and a J-edited PRESS sequence. Sequential MRS acquisitions each of 15 min duration (90 min total) were obtained before, during, and following the infusion. EEG was recorded using an MRI-compatible 64-channel system with direct current BrainAmp MR amplifiers (Brain Products GmbH). Post-ketamine EEG data were analyzed in frontal electrodes for gamma and delta alterations. EEG and MRS data were also acquired in 12 patients with SCH with these systems. Results Neurochemicals Glx and GABA showed acute increases within 15–30 minutes following the initiation of ketamine infusion, more pronounced for GABA (13% increase, p = .04 by paired t test). Gamma amplitude in left and right frontal electrodes increased in the first 15-minute average after initiation of ketamine (p < .05), with no evidence of earlier gamma decrease. Left delta amplitude decreased linearly following ketamine (p < .01). Peak GABA concentration correlated inversely with average left delta amplitude in the immediately subsequent 15-minute acquisition. Data in SCH showed similar elevations in GABA and gamma amplitude. Discussion These data show the feasibility of attaining time resolution of Glx and GABA changes in the several-minutes range with standard PRESS J-edited 1H MRS, and simultaneous sub-second resolution with EEG. There were no indications in these frontal electrodes of very early GABAergic inhibition leading to disinhibition of Glx, which may occur in other brain regions following ketamine administration. The GABA, Glx, and EEG alterations found here following ketamine administration are consistent with stable alterations reported in unmedicated patients with SCH and are compatible with an NMDA receptor deficit mechanism in the illness. They show homeostatic rebalancing at elevated levels as found in SCH itself. Excitation-inhibition rebalancing at abnormally elevated levels may pose a risk of neuronal damage that persists in untreated psychosis.

Overall Abstract: Evidence is accumulating that core features of schizophrenia (SCH) may arise from a fundamental disturbance in the cellular balance of excitation and inhibition (E-I balance) within neural circuitry. In the symposium, we will provide a comprehensive overview of E-I balance alterations in SCH with evidence from preclinical models and in vivo measurements investigating potential neurobiological mechanisms underlying these dysfunctions as well as interventions that remedy these disturbances. Takao Hensch will summarize findings on critical period plasticity and its potential role in vulnerability to schizophrenia. He will present new preclinical data on the destabilizing consequences of enhanced gamma oscillations, which reversibly prolong juvenile forms of brain plasticity by redox imbalance. Jan-Harry Cabungcal will address the role of redox dysregulation and oxidative stress in the pathophysiology of schizophrenia. He will present recent data on the relationship of deficits of the perineuronal net and oxidative stress in the anterior cingulate cortex, and evidence that redox dysregulation can be targeted with antioxidants/redox regulators across animal models. Lawrence Kegeles will present simultaneous EEG and proton MRS measurements of glutamate and GABA during ketamine administration in healthy young adults. These data will be compared with the same modalities acquired in individuals at clinical high risk and patients with SCH, showing disturbed delta and gamma band power and altered E-I balance despite homeostatic rebalancing of glutamate and GABA. Peter Uhlhaas will summarize evidence from EEG/MEG data examining the potential role of neural oscillations in the pathophysiology of schizophrenia. He will show that alterations in gamma-band oscillations are present prior to the onset of schizophrenia in at-risk individuals and related to aberrant E-I balance parameters revealed by MRS-measured levels of GABA and glutamate. Developmental data on the maturation of neural oscillations suggests that the transition from adolescence to adulthood is a sensitive period for modifications in neuronal dynamics that could potentially explain the manifestation of psychosis during this period.

Overall Abstract: Animal models of psychosis indicate a new focus on altered GABAergic neurotransmission as the source of subcortical dopamine dysfunction in schizophrenia. While neuroimaging research allows testing the relevance of these models in humans, the extent to which GABAergic neurotransmission is altered in patients with psychosis and people at clinical high risk for psychosis (CHR) is less clear. This symposium will address this issue by integrating findings from state-of-the-art preclinical research, neuropathology studies in schizophrenia, and human neuroimaging studies before and after the development of psychosis. Tony Grace (Pittsburgh) will describe preclinical evidence for a central role of prefrontal and hippocampal GABA interneuron dysfunction in the neurobiological cascade driving subcortical dopamine dysfunction and will show new data on the prevention of schizophrenia-like GABA cell loss by pharmacologically intervening on the GABAergic system. Francine Benes (Harvard) will report new neuropathological data on reduced hippocampal GABA interneurons in schizophrenia, which allow for a detailed understanding of corticolimbic GABAergic changes in the disorder and show specificity with regard to other psychotic disorders. Hilleke Hulshoff Pol (Netherlands) will present new findings on reduced prefrontal GABAergic function in patients with schizophrenia through magnetic resonance spectroscopy research, and its relationship with cognitive functioning. Finally, these data will be complemented by novel multimodal imaging evidence of alterations in prefrontal GABA levels and their relationship to hippocampal perfusion in CHR subjects, presented by Gemma Modinos (London). Philip McGuire, who leads one of the world’s largest groups working with neuroimaging in psychosis and high-risk groups, will integrate this set of complementary findings from different disciplines.