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

Activation of beta-adrenergic receptors (beta 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 beta 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 beta 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 beta 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 beta AR-mediated increases in cAMP accumulation are exclusively mediated by mGlu(3). Furthermore, mGlu(3) activation inhibits the ability of the beta 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 beta 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 beta AR-mediated effects on hippocampal synaptic plasticity and cognitive function.