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Man or mouse?

Day 3 of ECNP

It’s a strange thought – that while striving to understand the intricacies of the human mind, we often turn to a patient population who not only can’t discuss what they’re feeling with us but aren’t even the same species.

And yet, it’s an approach that is proven time and again to yield striking insights, as shown in the brainstorming session, “Bipolar disorder pathophysiology and treatment: insights from genetic animal models”, that kicked off Day 3 of ECNP.


The best laid plans oft go awry


Opening the session, Professor Catherine Belzung, gave us a brief introduction to the challenges that face researchers using animal models. As well as the difficult tasks of mimicking aetiology, symptomology, treatment outcomes and pathophysiology, Prof. Belzung highlighted the obstacle of behavioural phenotyping in bipolar disorder. With rapid cycling between manic and depressive states, she said, ups and downs in observed behaviour tend to cancel out to a flat-line, apparently showing no abnormality in the mouse subjects. She suggested overcoming this using live telemetry, allowing researchers an insight into the internal state of their subjects.


The hidden path


Prof. Belzung was followed by Doctor Claude Brodski, sharing his workgroup’s findings on the neurological underpinnings of bipolar disorder.

Dr. Brodski and team used OTX2 knockout mice to explore the role of monoaminergic neurons in bipolar. These OTX2 mutants, characterised by a reduced expression of serotonergic neurons, showed increased fluctuations in locomotor activity when observed in both home-cage and open-field environments. They also exhibited both increased risk-taking behaviours and reduced social interaction, symptomatic of both mania and depression.

Dr. Brodski found that therapies used for the treatment of bipolar disorder in humans could improve the behavioural alterations in the OTX2 mice. This, he suggested, points towards a possible mode of action for these therapies built around compensating for a deficit in serotonergic neuron expression. Exploring further, he discovered that bipolar sufferers showed a significant aggregated association of mutations in genes specifying monoaminergic neurons, an association not mirrored by schizophrenia or major depressive disorder.


Knockout effects


The introduction of underlying mechanisms was a topic common to our second speaker, Professor Galila Agam, whose aim was to uncover the molecular mechanism behind the mood-stabilising effects of lithium. Amongst the many pathways that lithium works upon, Prof. Agam chose to focus on three; the adenylyl cyclase pathway, the GSK-3β system of cell proliferation and the inositol monopole pathway in the PI cycle.

The first, AC, had initially been dismissed as a specific target due to the fact that it is so widely utilized across different systems of the body. Despite intriguing results in AC5 and AC7 gained after the discovery of AC isoforms, Prof. Agam agreed with this position, citing a lack of effect of absence of AC5-knockout on amphetamine-induced hyperlocomotion, a distinctive feature of lithium mood stabilisation.

GSK-3β, a popularly-supposed target of lithium, was discounted for a number of reasons, from lack of abnormal GSK-3β levels in diagnosed BPI patients to the absence of a lithium effect on glucose metabolism which would be implicit if GSK-3β was being acted on.

The most compelling case, argued Prof. Agam, was that of the inositol depletion hypothesis. This theory postulates a therapeutic effect from lithium’s known ability to enhance mitochondrial function, mediated by changes in inositol metabolism. Prof. Agam’s observation of lithium-like effects in inositol-knockout mice supported this theory, lending strength to the growing association of defective mitochondrial function with bipolar disorder.

As one of today’s participants noted, animal models will only ever be able to reflect individual facets of complex conditions such as bipolar disorder. But in a disease area where one patient can vary wildly from the next anyway, the ability to gain insights such as those on show today remains invaluable.

Continue the conversation on Twitter #ECNP2014

Our correspondent’s highlights from the symposium are meant as a fair representation of the scientific content presented. The views and opinions expressed on this page do not necessarily reflect those of Lundbeck.

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