GABA dysfunction – preclinical and clinical imaging perspectives in schizophrenia

Dr. Gemma Modinos presenting
GABA dysfunction at ECNP
Dr. Gemma Modinos
GABA dysfunction in the pathologenesis of schizophrenia
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Dr. Gemma Modinos
GABA dysfunction in the pathologenesis of schizophrenia

The association between abnormal interneuronal function and neuropsychiatric conditions is receiving growing attention. An interdisciplinary symposium given at this year’s ECNP, gave a comprehensive overview of GABA dysfunction in schizophrenia from a variety of perspectives.

Hippocampal hijacking

Anthony Grace, USA, presented the preclinical perspective of schizophrenia. As he explained, there is substantial evidence for the involvement of the dopaminergic (DA) system in schizophrenia, where it appears that the normal DA system is “hijacked” by other structures such as the hippocampus which are themselves hyperactive in schizophrenia.

MAM-treated rats were given an anxiolytic pre-pubertally which partially prevented PV neuronal loss in adult animals and prevented DA overdrive

Could pre-pubertal anxiolytic prevent adult psychosis?

Methylazoxymethanol acetate (MAM)-treated rats are a well-validated animal model of schizophrenia. These animals show an increased stress response both pre- and peri-pubertally and as adults. Intriguingly, in the pre-pubertal state there is loss of parvalbumin (PV) protein but not PV interneurons throughout the hippocampus of MAM-treated rats; in adults the PV neurons are lost.  As stress is known to cause a loss of PV interneurons in the hippocampus, MAM-treated rats were given an anxiolytic pre-pubertally to determine what the subsequent effects of stress might have in later life. The anxiolytic partially prevented PV neuronal loss in adult animals and prevented DA overdrive. Is this the animal equivalent of preventing psychosis?

MAM-treated rats were given an anxiolytic pre-pubertally which partially prevented PV neuronal loss in adult animals and prevented DA overdrive.

Schizophrenia and stress management

A basic inability to regulate stress early in life can lead to pathological changes in the hippocampus that may underlie the emergence of schizophrenia in adults

Converging evidence from clinical and basic science suggests that a basic inability to regulate stress early in life can lead to pathological changes in the hippocampus that may underlie the emergence of schizophrenia in adults. That MAM can be circumvented suggests that, while schizophrenia is a genetic predisposition, it is the environment that brings on the condition. This in turn suggests that major stressors during the critical peri-pubertal period can lead to PV loss and induce psychosis. As Dr Grace explained, timing is everything, but if this animal model reflects the human condition, if intervention occurs early enough in those individuals at clinical risk, we may be able to avoid or prevent the effects of stress and the transition to schizophrenia.

If intervention occurs early enough in those individuals at clinical risk, we may be able to avoid or prevent the transition to schizophrenia

A basic inability to regulate stress early in life can lead to pathological changes in the hippocampus that may underlie the emergence of schizophrenia in adults.

If intervention occurs early enough in those individuals at clinical risk, we may be able to avoid or prevent the transition to schizophrenia.

GABA

The post-mortem perspective on schizophrenia was given by Francine Benes, USA. She explained and presented evidence for the involvement of three GABAergic fibre systems, either alone or in combination, in the disinhibitory dysfunction within the hippocampus, specifically in the stratum oriens of sector CA3/2 of the hippocampus. Such dysfunction could have role both in schizophrenia and bipolar disorder.

Clinical imaging

Clinical imaging also help explain the role of GABA in schizophrenia. Gabriele Ende, Germany, explained how proton magnetic resonance spectroscopy (1H MRS) at field strengths above 7 Tesla allows the detection of GABA without the need for spectral editing. Currently, the findings from studies using lower strength GABA 1H MRS are heterogeneous but, as she pointed out, so are the groups studied in terms of their psychiatric disease, ages as well as the brain regions scanned.

BIG GABA

However, there is positive news. BIG GABA, a collaborative consortium of 24 research institutes using machines from 3 manufacturers, has discovered that GABA+ measurements show strong agreement when a standard protocol is implemented which may allow comparisons between studies to be made at lower field strengths.

GABA imaging and impulsivity

Additional potential lies in multimodal combinations of fMRI, morphometry, diffusion and metabolism studies to generate a more complete picture of neuropsychological correlates with neurochemical functioning and structural brain architecture.  For example, a recent MRS/fMRI study showed that GABA system within the anterior cingulate cortex is associated with regional BOLD activation and functional connectivity within this network; this activity is also associated with impulsiveness in borderline personality disorder (BPD). Dr Benes suggested working memory might be a potential avenue to consider in schizophrenia.

Hippocampal perfusion and psychosis

Medial prefrontal cortex GABA+ was directly associated with hippocampal perfusion; this association was strongest in patients who developed psychosis

Gemma Modinos, UK, presented GABA imaging data gathered from 36 people considered at high clinical risk of psychosis. Her group found that medial prefrontal cortex GABA+ was directly associated with hippocampal perfusion. Importantly, this association was strongest, albeit in a small subset, of patients who developed psychosis.  Could this be one way to identify those at highest risk and to possibly identify a means to prevent onset of full-blown symptoms?

Medial prefrontal cortex GABA+ was directly associated with hippocampal perfusion; this association was strongest in patients who developed psychosis.

References
  1. Benes FM. Amygdalocortical circuitry in schizophrenia: from circuits to molecules. Neuropsychopharmacology. 2010 Jan;35(1):239-57.
  2. Du Y, Grace AA. Loss of Parvalbumin in the Hippocampus of MAM Schizophrenia Model Rats Is Attenuated by Peripubertal Diazepam. Int J Neuropsychopharmacol. 2016 Dec 3;19(11). pii: pyw065.
  3. Du Y, Grace AA. Amygdala Hyperactivity in MAM Model of Schizophrenia is Normalized by Peripubertal Diazepam Administration. Neuropsychopharmacology. 2016 Sep;41(10):2455-62.
  4. Gomes FV, Grace AA. Prefrontal Cortex Dysfunction Increases Susceptibility to Schizophrenia-Like Changes Induced by Adolescent Stress Exposure. Schizophr Bull. 2017 May 1;43(3):592-600.
  5. Ende G. Proton Magnetic Resonance Spectroscopy: Relevance of Glutamate and GABA to Neuropsychology. Neuropsychol Rev. 2015 Sep;25(3):315-25.
  6. Gill KM, Grace AA. Corresponding decrease in neuronal markers signals progressive parvalbumin neuron loss in MAM schizophrenia model. Int J Neuropsychopharmacol. 2014 Oct;17(10):1609-19.
  7. Hayes DJ, Jupp B, Sawiak SJ, Merlo E, Caprioli D, Dalley JW. Brain γ-aminobutyric acid: a neglected role in impulsivity. Eur J Neurosci. 2014 Jun;39(11):1921-32.
  8. Paredes RG, Agmo A. GABA and behavior: the role of receptor subtypes. Neurosci Biobehav Rev. 1992 Summer;16(2):145-70.
  9. Tkác I, Oz G, Adriany G, Uğurbil K, Gruetter R. In vivo 1H NMR spectroscopy of the human brain at high magnetic fields: metabolite quantification at 4T vs. 7T. Magn Reson Med. 2009 Oct;62(4):868-79.
  10. Wang GY, van Eijk J, Demirakca T, Sack M, Krause-Utz A, Cackowski S, Schmahl C, Ende G. ACC GABA levels are associated with functional activation and connectivity in the fronto-striatal network during interference inhibition in patients with borderline personality disorder. Neuroimage. 2017 Feb 15;147:164-174.
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