Concomitant Deficits in Working Memory and Fear Extinction Are Functionally Dissociated from Reduced Anxiety in Metabotropic Glutamate Receptor 7-Deficient Mice

Abstract

Metabotropic glutamate receptor 7 (mGluR7), a receptor with a distinct brain distribution and a putative role in anxiety, emotional responding, and spatial working memory, could be an interesting therapeutic target for fear and anxiety disorders. mGluR7-deficient (mGluR7 Ϫ/Ϫ ) mice showed essentially normal performance in tests for neuromotor and exploratory activity and passive avoidance learning but prominent anxiolytic behavior in two anxiety tests. They showed a delayed learning curve during the acquisition of the hidden-platform water maze, and three interspersed probe trials indicated that mGluR7 Ϫ/Ϫ mice were slower to acquire spatial information. Working memory in the water maze task and the radial arm maze was impaired in mGluR7 Ϫ/Ϫ mice compared with mGluR7 ϩ/ϩ . mGluR7 Ϫ/Ϫ mice also displayed a higher resistance to extinction of fear-elicited response suppression in a conditioned emotional response protocol. In a non-fear-based water maze protocol, mGluR7 Ϫ/Ϫ mice displayed similar delayed extinction. These observed behavioral changes are probably not attributable to changes in AMPA or NMDA receptor function because expression levels of AMPA and NMDA receptors were unaltered. Extinction of conditioned fear is an active and context-dependent form of inhibitory learning and an experimental model for therapeutic fear reduction. It appears to depend on glutamatergic and higher-level brain functions similar to those involved in spatial working memory but functionally dissociated from those that mediate constitutional responses in anxiety tests.

mGluR7 facilitates extinction of aversive memories and controls amygdala plasticity

“…48 Our findings of retarded extinction subsequent to siRNA-induced mGluR7 knockdown is in agreement with recent studies demonstrating that mice deficient in mGluR7 have deficits in the extinction of a conditioned emotional response. 11 Furthermore, our siRNA data also confirm that such deficits are unlikely to be due to developmental compensations resulting from lifelong absence of mGluR7.…”

“…9 Studies on mGluR7-deficient mice have pointed towards a key role for this receptor in models of innate fear as well as in learned, amygdala-dependent anxiety-related responses. [10][11][12] Further progress in understanding this receptor's role in the acquisition and/or extinction of conditioned fear has been hampered by the lack of pharmacological tools. Recently, we developed the first mGluR7-selective allosteric agonist AMN082, which we have shown to be a potent activator of human mGluR7.…”

Mechanisms of fear extinction

“…Within the amygdala, mGluR7 is localized to presynaptic terminals of glutamatergic neurons 179 and may act to inhibit glutamate release. 180 Callaerts-Vegh et al 181 compared mGluR7À/À mice with mGluR7 þ / þ littermate controls on a variety of tasks, including a conditioned emotional response (CER) procedure in which tone-shock pairings were introduced while the animals performed a previously trained nose-poke task in which nose pokes were reinforced by delivery of food pellets. Both groups of animals learned to nose poke equally well and both came to suppress nose poking during tone presentations equally quickly.…”

Upregulation of Calcium/Calmodulin-Dependent Protein Kinase IV Improves Memory Formation and Rescues Memory Loss with Aging

“…In these behavioral tests, mice were trained using normal training protocols (Kogan et al, 2000;Callaerts-Vegh et al, 2006;Suzuki et al, 2008).…”