9 May 2017
As part of our ongoing coverage of the 2017 International Congress on Schizophrenia Research (ICOSR), held March 25-28 in San Diego, we bring you session summaries from some of the awardees of the Young Investigator travel grants. We are, as always, grateful for the gracious assistance of YI program directors Laura Rowland and Scott Sponheim, as well as Michelle Tidwell of the ICOSR staff. For this report, we thank Dibyadeep Datta of Yale University.
Dysfunction in the principal inhibitory neurotransmitter system in the brain, GABA, is a long-standing interest in the field of neuroscience and is particularly relevant to neuropsychiatric disorders since it has been implicated in the pathophysiology of schizophrenia. This notion has been supported by several lines of evidence, including postmortem examinations of neural circuitry, promising explorations in rodent model systems, and neuroimaging studies in human subjects. However, from a therapeutic standpoint, the dopamine system has been the primary focus in treating the symptoms of the disorder. While antagonism of dopamine D2 receptors with typical and atypical antipsychotics is able to ameliorate, to some degree, the positive symptoms of schizophrenia, it has little to no effect on the negative and cognitive symptoms. As a result, there is an increasing impetus to identify novel drug targets to treat these symptoms of patients with schizophrenia. In order to tackle this issue, a multidisciplinary panel of researchers presented their findings regarding the role of GABA dysfunction in schizophrenia at the International Congress on Schizophrenia Research annual meeting in San Diego, in a symposium titled “Entraining Neural Networks Through Parvalbumin-Positive Interneurons: Can This Offer a Better Way to Treat Schizophrenia?”
The first talk was presented by David Lewis of the University of Pittsburgh, who elegantly described a constellation of findings from postmortem tissue, which suggests a central role of dysregulated GABA neurotransmission in the pathogenesis of schizophrenia. His work focused on the dorsolateral prefrontal cortex (DLPFC), which is critical for higher-order cognitive functions such as working memory. His work has identified a particular subclass of GABA interneurons that expresses the calcium-binding protein parvalbumin (PV), and appears to be particularly susceptible in the disease. PV interneurons are fast-spiking inhibitory cells that are able to innervate multiple pyramidal cells within their vicinity and thus rhythmically modulate neural ensembles, particularly in the gamma-frequency range (30-80 Hz), which is impaired in schizophrenia under task-evoked conditions. Lewis’ research suggests that although there are no differences in PV cell density between control and schizophrenia subjects, the expression levels of the principal enzyme that synthesizes GABA, GAD67, are lower in a subset of PV cells, which is predicted to result in decreased synthesis and release of GABA. Moreover, laser-capture microdissection of PV interneurons in DLPFC has revealed robust impairments in oxidative phosphorylation and mitochondrial pathways, indicating that these cells are hypofunctional.
Lewis's work, in collaboration with Takanori Hashimoto from Kanazawa University, also revealed significant downregulation of the gene KCNS3, encoding the Kv9.3 potassium channel α-subunit, which assembles with the delayed rectifier Kv2.1 α-subunits. The heteromeric Kv2.1/Kv9.3 channels permit the detection of coincident inputs needed for excitatory postsynaptic potential (EPSP) decay in PV cells, allowing precise control of pyramidal cell activity needed for gamma-frequency oscillations. Furthermore, other molecular disturbances in PV cells include dysregulated ErbB4 splicing, which is crucial for clustering of excitatory synapses, resulting in fewer excitatory inputs to PV cells. These disturbances might reflect intrinsic alterations in PV cells, or activity-dependent changes in response to proximal impairments in DLPFC pyramidal cells. These are ideas that remain to be tested and are imperative in disentangling cause-consequence relationships in schizophrenia. Either way, enhancing PV cell activity might provide a compensatory strategy to restore cognitive function in patients.
The next speaker, Carol Tamminga of the University of Texas Southwestern Medical Center, presented the provocative findings from the Bipolar-Schizophrenia Network on Intermediate Phenotypes (B-SNIP) consortium. Using sophisticated statistical approaches, the project's researchers were able to delineate psychiatric patients based on the underlying neurobiology rather than the traditional, symptom-based diagnostic domains. As part of the project, the multisite research team assessed biological and behavioral measures from 1,872 subjects (schizophrenia, schizoaffective, and bipolar disorder with psychosis; first-degree relatives; healthy comparison subjects). Using multivariate taxometric analyses, they were able to identify three biologically unique subtypes (referred to as biotypes 1-3), which differed significantly from the parcellation of subjects based on clinical phenomenology (see SRF news story). Each biotype had unique biomarker characteristics in the areas of cognition, oculomotor function, and magnetic resonance imaging (MRI) and electroencephalogram (EEG) traits. For example, subjects who were clustered into biotype 1 had the most profound deficits in cognitive control, neural responsiveness to sensory stimulation, and a hypoactive EEG profile. In contrast, subjects clustered in biotype 2 exhibited significant but less severe cognitive control dysfunction with accentuated sensorimotor reactivity and elevated EEG profile indicative of hyperactivity.
The proof-of-principle method of segregating patients into biologically meaningful subgroups has potential for biotype-specific pharmacotherapy. For example, patients in biotype 2 might be pursued for drugs that enhance GABA activity to homeostatically restore the hyperactive EEG profile. This is consistent with the previous work from the Tamminga laboratory that highlighted the critical role of voltage-gated Kv3.1 channels on PV interneurons in entraining pyramidal cell ensembles, since Kv3.1 deficiency is associated with hypoactive PV cells and is predicted to result in hyperactive EEG profiles. Therefore, positive allosteric modulators of Kv3.1 channels might be a plausible target for intervention in patients who cluster in biotype 2.
In keeping with this theme, Charles Large of United Kingdom-based Autifony Therapeutics presented some very interesting preclinical data based on the novel Kv3.1-selective positive modulator, AUT00206. The drug specifically targets the Kv3.1 channel that is predominantly localized on PV interneurons. The efficacy of the drug was first tested in vivo in a subchronic phencyclidine (scPCP) model of schizophrenia, where it was found to rescue short-term memory deficits, reverse impairments in reversal learning, and enhance social interaction. AUT00206 also prevented amphetamine-induced hyperactivity in rodent models. Electrophysiological studies in vitro in prefrontal cortical slices showed that AUT00206 enhanced kainite-induced gamma-frequency oscillations from scPCP rats. These preclinical findings served as the basis for a Phase 1 double-blind, randomized clinical study to determine pharmacokinetics of AUT00206 and assessed whether administration of the drug was associated with rescue of a clinical phenotype in schizophrenia patients. Indeed, the clinical study established safety and tolerability of the drug, and showed concentration-dependent enhancement of mismatch negativity, an auditory event-related potential that provides an index of context-dependent information processing and auditory sensory memory. The mismatch negativity is a robust abnormality in chronic patients with schizophrenia, and the enhancement effects of AUT00206 suggest that it might be a credible therapeutic strategy to treat the symptoms of the disease.
The potential of targeting the GABAergic neurotransmitter system was supported by neuroimaging studies presented by Philip McGuire of King’s College London. McGuire presented some encouraging findings from patients at ultra-high risk (UHR) for psychosis by examining the relationship among GABA, glutamate, and dopamine levels in these patients, and assessing the risk for development of later-onset psychosis. Using magnetic resonance spectroscopy (MRS), positron emission tomography (PET) and arterial spin labeling (ASL), his group found significant differences in GABA levels in the prefrontal cortex in UHR subjects and dopamine levels in midbrain and basal ganglia circuits. Moreover, within UHR subjects, there were significant correlations between hippocampal glutamate levels and striatal dopamine. The in vivo neuroimaging data support the idea that dysregulation of GABA and glutamate systems precedes dopamine dysfunction, which predicts the risk of progression to psychosis in UHR patients.
In summarizing the overarching theme of the symposium, the discussant Bill Potter, an advisor to the US National Institute of Mental Health, made the argument that the discovery of novel interventions for schizophrenia requires a strategy for prioritizing drug targets, based on a thorough understanding of the underlying neurobiology of the disorder rather than pursuing conventional diagnostic categories to inform drug development. The approach presented in the symposium validates the Research Diagnostic Criteria (RDoC) initiative and might lead to more precise therapeutic interventions for subgroups of patients. In aggregate, the data presented at ICOSR 2017 reinforce the idea that GABA interneurons, specifically PV cells, might be key players in the disease process and that targeting these cells might alleviate, at least in part, the symptoms of schizophrenia.