Co-Activation of Metabotropic Glutamate Receptor 3 and Beta-Adrenergic Receptors Modulates Cyclic-AMP and Long-Term Potentiation, and Disrupts Memory Reconsolidation

Activation of β -adrenergic receptors ( β ARs) enhances both the induction of long-term potentiation (LTP) in hippocampal CA1 pyramidal cells and hippocampal-dependent cognitive function. Interestingly, previous studies reveal that coincident activation of group II metabotropic glutamate (mGlu) receptors with β ARs in the hippocampal astrocytes induces a large increase in cyclic-AMP (cAMP) accumulation and release of adenosine. Adenosine then acts on A 1 adenosine receptors at neighboring excitatory Schaffer collateral terminals, which could counteract effects of activation of neuronal β ARs on excitatory transmission. On the basis of this, we postulated that activation of the specific mGlu receptor subtype that mediates this response could inhibit β AR-mediated effects on hippocampal synaptic plasticity and cognitive function. Using novel mGlu receptor subtype-selective allosteric modulators along with knockout mice we now report that the effects of mGlu 2/3 agonists on β AR-mediated increases in cAMP accumulation are exclusively mediated by mGlu 3 . Furthermore, mGlu 3 activation inhibits the ability of the β AR agonist isoproterenol to enhance hippocampal LTP, and this effect is absent in slices treated with either a glial toxin or an adenosine A 1 receptor antagonist. Finally, systemic administration of the mGlu 2/3 agonist LY379268 disrupted contextual fear memory in a manner similar to the effect of the β AR antagonist propranolol, and this effect was reversed by the mGlu 3 -negative allosteric modulator VU0650786. Taken together, these data suggest that mGlu 3 can influence astrocytic signaling and modulate β AR-mediated effects on hippocampal synaptic plasticity and cognitive function.