‘Distinct’ bipolar pathways revealed

By Eleanor McDermid, Senior medwireNews Reporter

A genetic analysis reported in Nature suggests two mechanisms that could lead to bipolar disorder.

One mechanism is dysfunction of the well-established glycogen synthase kinase 3 pathway, which responds to standard mood-stabilizing treatment. The other is “synaptic dysfunction associated with an E/I [excitatory/inhibitory] balance shifted towards excitation, which could result in hyperkinetic behaviours,” say study author Huda Zoghbi (Baylor College of Medicine, Houston, Texas, USA) and co-workers.

This type of process may underlie mania in patients with rapid-cycling bipolar disorder, who are difficult to treat, they suggest.

They draw their conclusions from their research using a mouse model that overexpresses SHANK3, a gene that encodes a scaffolding protein involved in assembling complexes at the postsynaptic density. Mutations and deletions affecting SHANK3 have been implicated in human psychiatric disorders, but this is the first direct evidence that its overexpression is also deleterious, says the team.

The mice were hyperactive, and this behavior was exacerbated, rather than decreased, by stimulant treatment, which is characteristic of mania. And on further study, the mice scored more highly than wild-type mice in tests of behaviors observed in people during manic episodes.

The team also used a genetics database to identify two patients with very small duplications in chromosome 22 that included SHANK3. One patient had bipolar disorder and epilepsy and the other was diagnosed with combined-type attention deficit hyperactivity disorder, had seizures, and was resistant to stimulant treatment.

“The remarkable similarity of the neurobehavioural phenotypes between the mouse model and patients with SHANK3 duplications supports the notion that SHANK3 overexpression causes a hyperkinetic neuropsychiatric disorder that approximates mania,” say the researchers.

They also found that the synaptic E/I balance in the mice was shifted towards excitation, explaining why they had spontaneous seizures, as did the two patients with overexpressed SHANK3. The shift in the mice was due to increased F-actin levels.

Although the manic behavior of the mice was not decreased by treatment with mood stabilizers, they did respond to treatment with an anti-epileptic drug that is also approved to treat manic and mixed episodes, supporting the notion of two distinct pathways to mania.

“[O]ur study advances our understanding of the human diseases associated with SHANK3 and the mechanisms that can lead to bipolar disorder,” say Zoghbi et al.

They add: “We believe this sort of pharmacogenetic analysis in model organisms could improve treatment strategies for patients with bipolar disorder as the genetic underpinnings of each patient’s illness are elucidated.”

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