Studies of the G-protein-coupled receptor NTSR1 show that the G protein selectivity of this receptor can be modified by small molecules, enabling the design of drugs that work by switching receptor su...

Hemispheric asymmetries in NMDAR-dependent synaptic plasticity have been described in hippocampal area CA1, but it remains unclear whether similar lateralized mechanisms exist for cyclic adenosine monophosphate (cAMP)-dependent plasticity. Here, we investigated whether cAMP-mediated potentiation of synaptic transmission in mouse CA1 exhibits hemisphere-specific properties. In recordings with electrical stimulation of CA1 inputs, a subset of recordings in the left, but not in the right hemisphere CA1, exhibited a pronounced cAMP-induced potentiation of field excitatory postsynaptic potentials (fEPSPs). To isolate input-specific contributions, we expressed the optogenetic actuator ChrimsonR unilaterally in the CA3/CA2 region of wild-type mice. Light-evoked glutamate release from ipsilateral Schaffer collaterals showed no cAMP sensitivity in either hemisphere, while commissures originating from the right (COR) exhibited cAMP-mediated potentiation of transmission in a subset of experiments. Notably, this effect was absent at commissures originating from the left (COL). The selective presence of the effect prompted us to further investigate the underlying cell population using CA3-specific (G32-4 Cre) and CA2-specific (Amigo2-Cre) driver lines. Recordings from synapses of CA3 COR recapitulated the cAMP-induced potentiation of transmitter release observed in wild-type animals. However, the effect was again restricted to a subset of experiments, did not correlate with the age or the sex of the mice, and was absent in recordings with specific stimulation of CA2 COR. Our results demonstrate a variable cAMP sensitivity of synaptic transmission at COR synapses in the left CA1. Altogether, we reveal a hemisphere-specific cAMP-mediated synaptic plasticity at CA3 COR onto CA1, underscoring hidden heterogeneity and lateralization in hippocampal circuit function.