Disturbed glutamatergic function may be involved in the aetiology of depression. In the search for new antidepressant targets, basic scientists are using animal models to investigate signaling events downstream from the NMDA receptor. The JNK pathway and neuronal nitric oxide synthases are of particular interest.
Might JNK inhibitors have therapeutic potential?
The JUN amino terminal kinases (JNK) are activated by cellular stress and play a part in apoptosis. Genetic susceptibility to psychiatric disorders in humans is associated with disruption of JNK pathway signalling, and this stress kinase appears to regulate anxiety and depression-like behaviours in mice. JNK1 plays an active role in the developing brain. It is also expressed in adulthood, but we know less about its role. Even so, might JNK inhibitors have therapeutic potential?
This is the question being asked by Eleanor Coffey, University of Turku, Finland.
JNK1 knockout animals display less anxiety than wild type animals. Dr Coffey and colleagues were not able to show that acute inhibition of JNK1 altered anxiety behaviour. But chronic treatment with an inhibitor decreased “anxious” behaviour in adult mice and increased neurogenesis in the hippocampus. In patients, hippocampal neurogenesis is required for the action of antidepressants; so this phenomenon may be relevant to treatment. In Dr Coffey’s model, if mitosis is blocked by administration of Ara-C, the anxiolytic effect of the inhibitor is reduced.
Inhibition of JNK in the neurogenic niche also alleviates “depressed” behaviour modelled by the forced swim test. Inhibition of nuclear JNK in the newborn granule cells of the dentate gyrus is sufficient to induce a non-anxious phenotype and alleviate depressive behaviour.
Ketamine without the adverse events?
Might agents that act downstream of the NMDA receptor give us the antidepressant efficacy of ketamine without that agent’s adverse effects? Modifiers of NMDA signalling are putative antidepressants, Andrew Harkin (Trinity College Dublin, Ireland) told the meeting. For that reason, he has been investigating nitric oxide (NO) synthase inhibitors. Such inhibitors appear to have antidepressant-like effects in the forced swim paradigm.
Dr Harkin has been using the Wistar Kyoto rat, an inbred strain with a marked depressive phenotype and a demonstrable reduction in hippocampal volume. The imidazole NO synthase inhibitor TRIM has an antidepressant effect in this model and also appears able to reverse the reduction in neural complexity induced by NMDA.
Test compounds in rodent models have a delayed but sustained antidepressant effect. The delay suggests a novel mechanism involving neuroplasticity. Such agents may have problematic off-target effects on the vasculature, so we need new compounds which are selective for NO synthase on the NMDA receptor. But the NO synthase/NMDA interface remains a potentially interesting target.
Life as a lonely rat
Early neglect is a risk factor for depression in humans. And Kevin Fone, of the Queen’s Medical Centre, University of Nottingham, UK, has been using a model in which rats are reared from weaning in social isolation. This has adverse effects on the animals, which are sociable by nature, and leads to a range of abnormalities including hyperactivity in novel environments and deficits in memory and associative learning.
Current anxiolytic agents can reverse the “anxious” behaviour of animals placed in an unfamiliar cage, and Dr Fone was able to show that a 5-HT6 antagonist could reverse the cognitive impairments seen in animals reared in isolation..
Also relevant is the fact that rats reared in social isolation show reduced volume of the medial prefrontal cortex similar to that seen in people with depression.
Such findings suggest that this rodent model of neurodevelopment might be useful in screening new compounds for therapeutic potential.