Elsevier

Brain Research Bulletin

Volume 48, Issue 5, 15 March 1999, Pages 467-473
Brain Research Bulletin

Review Articles
GABA-ergic neurons and the neurobiology of schizophrenia and other psychoses

https://doi.org/10.1016/S0361-9230(99)00025-8Get rights and content

Abstract

There are a number of disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM IV) that are characterised by having psychotic symptoms as the defining feature [17]. The narrowest definition of psychosis is restricted to delusions or prominent hallucinations, with the hallucinations occurring in the absence of insight into their pathological nature. Schizophrenia is the most prevalent form of psychosis, but this may also occur due to other medical conditions (e.g., Prader-Willi syndrome, epilepsy), in the early post-partum period, at menopause, and as a result of drug use. This article attempts to draw together an underlying causation across the various forms of psychotic disorder and, by integrating this with what is known about the genetics, neuroanatomy and neuropharmacology of the positive symptoms in schizophrenia, produce a broader understanding. At the cellular level, gamma-aminobutyric acid (GABA)-ergic interneurons are a common feature in psychotic states, and are a principal focus for serotonin and dopamine innervations, as well as playing an important role in cortical development. At the systems level, prefrontal and medial temporal cortices are implicated with activity levels out of synchrony in schizophrenics. How these vast areas of disparately functioning cortical networks are “bound” together to provide coherent conscious experiences is again a function of GABA-ergic interneurons. These interneurons have highly divergent inhibitory projections to large numbers of pyramidal neurons and are themselves synchronised by the ascending dopamine and serotonin innervations.

Section snippets

Cortical GABA-ergic neurons, dopamine receptors, and schizophrenia

Chandelier cells are gamma-aminobutyric acid (GABA)-ergic interneurons with a unique synaptic specificity enabling them to exert a strong inhibitory influence on pyramidal cells [14]. They are located in all regions of the hippocampal formation, temporal neocortex, and prefrontal cortex. The chandelier GABA-ergic neurons are a distinct type of inhibitory interneuron the axon terminals of which form arrays or “cartridges,” which provide inhibitory input exclusively to the axon initial segment of

Epilepsy

It is commonly accepted that people with epilepsy have more psychiatric problems than those without epilepsy. In particular, non-affective psychosis is increased in men and women with epilepsy, and this pathogenic association has been found both in selected patient populations and from more extensive epidemiological studies [9]. Several investigations have found an excess of temporal lobe epilepsy [5] among people with psychosis and epilepsy, while others have registered psychosis due to

Psychosis—a disorder of neurodevelopment

The view that schizophrenia is a disorder of brain development has received considerable attention in recent years [27]. A number of these reports have pointed to structural changes in the cortex including neurons being misplaced, and asymmetry of the cortex being reduced in schizophrenics. Moreover, children at risk of developing schizophrenia show delayed neurological development, while there is an increased incidence of cerebral anomalies such as agenesis of the corpus collosum in

GABA-ergic neurons and cortical development

The cells of the cerebral cortex, both neurons and glia originate from the ventricular zone and sub-ventricular zone in the developing telencephalon [38]. The predominant mode of cell migration into the cerebral cortex is both radially and clonally based [47], but recent studies have revealed a sub-population of neocortical interneurons that express GABA and migrate from the developing striatum [49]. This cell migration occurs between the primordia of the basal ganglia and cerebral cortex,

Psychosis: functional imaging of the brain

Brain imaging in schizophrenia has provided important evidence that the disorder is associated with disturbances in cerebral structure. Computerised tomography (CT) provided the early evidence for enlarged ventricular size. Magnetic resonance imaging (MRI) with its greater resolution has tended to confirm these early findings [54] and extend them to specific cerebral structures [20]. Decreases in size of the pre-frontal lobe, temporal lobe and amygdala have also been reported. However, it

GABA-ergic interneurons—importance for “binding” and synchronisation of neural networks

In the early 1980s it was proposed on theoretical grounds that assemblies of synchronously firing neurons may provide the basic building blocks of neuronal representations. Several important studies have gone some way to support this viewpoint 23, 48. Neuronal activity in the frontal cortex of monkeys can show a systematic relationship to behavioural events, and synchronisation of neuronal activity rather than the level of activity itself seems to be the important correlate [61]. For the visual

Conclusions

This review has provided compelling evidence for a pivotal role of cortical GABA-ergic interneurons in psychoses of the kind seen in schizophrenia, at menopause and post-partum, as a result of drug abuse, and secondary to other medical conditions such as epilepsy and Prader-Willi syndrome. This does not provide an alternative to the dopamine hypothesis or rule out the involvement of other transmitters such as serotonin and glutamate, but integrates these transmitters with GABA-ergic

Acknowledgements

This work was supported by MRC Brain, Behaviour and Neuropsychiatry co-operative. I would like to thank James Leckman for his stimulating discussion that generated much of the thinking behind this review.

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