Adult siRNA-induced knockdown of mGlu7 receptors reduces anxiety in the mouse.

摘要

Our knowledge regarding the molecular pathophysiology underlying anxiety disorders remains incomplete. Increasing evidence points to a role of glutamate in anxiety. The group III metabotropic glutamate receptors (mGlu4, mGlu6, mGlu7 and mGlu8 receptors) remain the least investigated glutamate receptor subtypes partially due to a delay in the development of specific pharmacological tools. Early work using knockout animals and pharmacological tools aimed at investigating the role of mGlu7 receptor in the pathophysiology of anxiety disorders has yielded exciting yet not always consistent results. To further investigate the role this receptor plays in anxiety-like behaviour, we knocked down mGlu7 receptor mRNA levels in the adult mouse brain using siRNA delivered via an osmotic minipump. This reduced anxiety-like behaviour in the light-dark box coupled with an attenuation of stress-induced hyperthermia (SIH) and a reduction of the acoustic startle response (ASRs) in the fear-potentiated startle paradigm (FPS). These effects on anxiety-like behaviour were independent of any impairment of locomotor activity and surprisingly, no behavioural changes were observed in the forced swim test (FST), which is in contrast to mGlu7 receptor knockout animals. Furthermore, the previously reported epilepsy-prone phenotype seen in mGlu7 receptor knockout animals was not observed following siRNA-induced knockdown of the receptor. These data suggest targeting mGlu7 receptors with selective antagonist drugs may be an effective and safe strategy for the treatment of anxiety disorders.