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Rhythm and Blues: An ECNP symposium on GABAergic dysfunction

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The speakers in this fascinating morning session discussed some basic functions of neuronal networks in the hippocampus. There was a particular emphasis, given the subject of the symposium, on GABAergic interneuron networks, and their possible involvement in mood disorders.

Tapping into the rhythm

 

The first speaker, Prof Imre Vida, from the Institute of Integrative Neuroanatomy at the Charité here in Berlin, started with an overview of the rhythmical electrical activity of the brain. EEGs were first measured nearly 100 years ago. These brain rhythms fascinated researchers because of their variability, which was in such contrast to the uniform rhythmical activity of the heart. In the last 20–30 years, research into these EEG rhythms has allowed us to characterize components that are related to different higher cognitive functions. So, for example, the low-frequency theta rhythm has been associated with spatial navigation and working memory, whereas the higher frequency gamma rhythm has been mapped to activities such as visuomotor integration, attention and short-term memory.

 

The pacemaker of the brain

 

Glutamatergic pyramidal cells are the backbone of information processing in cortical structures, but their rhythmic activity seems to be driven and coordinated by GABAergic interneurons. These cells show mutual inhibition, as well as inhibiting glutamatergic neurons. The interneuron–interneuron interactions act to synchronise activity of the GABAergic networks, allowing them to act as ‘pacemaker’ networks that can entrain activity throughout the system they affect.

Prof Vida presented evidence that marked EEG rhythm changes in experimental animal models of temporal lobe epilepsy were produced by small changes in the electrophysiology of GABAergic interneurons. Differences in gamma rhythm have also been seen in animals during and after pregnancy. Dr Vida speculated that post-partum problems such as depression and seizures may be related to these changes in oscillation of neuronal networks.

 

Facing our fears

 

Professor Rainer Rupprecht from the University of Regensburg presented further evidence for the involvement of GABAergic networks in the mood disorders, and pointed to possible novel therapies affecting this system. He stated that neurosteroids have powerful effects on GABAA receptors, and therefore (like the benzodiazepines, which directly modulate these receptors) have potential anxiolytic activity. Ligands of the catchily named translocator protein 18 kDa (TSPO) do not affect the GABAA receptor directly, but have potential anxiolytic activity through their effects on the production of neurosteroids.

 

Don’t panic!

 

In animal models of anxiety, a TSPO ligand produced anxiolytic effects and, importantly, little sedation and tolerance – well known problems associated with many currently used anxiolytic agents. These anxiolytic effects of a TSPO ligand have also been shown in small numbers of healthy volunteers subjected to the somewhat alarming sounding induced-panic tests. Moreover, in patients with panic disorder who were given a panic-inducing agent, there is a reduction in neurosteroids, which indicates that a reduction in GABAergic tone may contribute to panic activity in humans. This provides a rationale for further research into the use of agents affecting neurosteroids in panic disorder.

 

Ain’t no sunshine when you’re gone

 

The fact that hippocampal volume decreases in depression is a well established finding in biological psychiatry. Dr Boldizsár Czéh of the University of Pécs, Hungary, presented evidence that may provide a link between hippocampal atrophy and changes in some of the GABAergic interneurons (specifically, parvalbumin-binding cells) in this area.

Dr Czéh introduced several animal models of chronic stress that mimic some of the environmental causes and behavioural effects of depression in humans. Following chronic stress, animals showed a reduction in the number of PV-binding GABAergic interneurons, which could be restored by treatment with an SSRI. Interestingly, the reduction in hippocampal neurogenesis that was produced by chronic mild stress in animals could also be blocked by an SSRI. These results add further weight to the theories positing GABAergic dysfunction as part of the aetiology of depression.

Disclaimer: Dysfunctional GABAergic networks in psychiatric disorders’ was an ECNP scientific symposium. Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented.
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