Metabotropic glutamate receptor 7: at the interface of cognition and emotion

Abstract

Understanding the complex interaction between stress and genetics that leads to the manifestation of disorders such as depression, anxiety, and cognitive dysfunction is one of the key areas of research in modern neuroscience. Growing evidence suggests that the glutamatergic system may be a relevant therapeutic target for such disorders. Glutamate is the neurotransmitter at the vast majority of excitatory synapses in the brain, and metabotropic glutamate (mGlu) receptor subtypes (mGlu(1) receptor-mGlu(8) receptor) act as important pre- and postsynaptic regulators of neurotransmission in the central nervous system (CNS), providing a mechanism by which fast synaptic responses through ligand-gated cation channels can be fine-tuned. Thus mGlu receptors are poised to participate in a wide variety of functions of the CNS. The presynaptic mGlu(7) receptor shows the highest evolutionary conservation within the family and it is thought to regulate neurotransmitter release. The mGlu(7) receptor is also the most widely distributed of the presynaptic mGlu receptors and is present at a broad range of synapses that are postulated to be critical for both normal CNS function and a range of psychiatric and neurological disorders. A growing body of evidence suggests that the mGlu(7) receptor is a key player in shaping synaptic responses at glutamatergic synapses as well as being a key regulator of inhibitory GABAergic transmission. The development of selective pharmacological and genetic tools has allowed for the unravelling of mGlu(7) receptor function in a host of physiological and behavioural processes. Knockout mice and siRNA knockdown has pointed to a role of the mGlu(7) receptor in anxiety, extinction of fear and aversion learning, spatial memory and the hormonal response to stress. In addition, these studies are largely supported by pharmacological manipulation of mGlu(7) receptor using the selective modulator N,N'-dibenzhydrylethane-1,2-diamine dihydrochloride (AMN082), although paradoxical effects with this agonist have also emerged. Together these data suggest that the mGlu(7) receptor is an important regulator of glutamatergic function, of fear and aversion and cognition and thus this receptor represents an innovative therapeutic target for stress-related disorders at the interface of cognition and anxiety.