THE IMPACT OF PHOSPHODIESTERASES ON SYNAPTIC FUNCTION​

The cyclic nucleotides cAMP and cGMP are known to play important roles in synaptic function in different brain areas. For instance, cAMP has long been shown to play a part in long-term potentiation (LTP) at the Schaffer collateral synapses of the hippocampus (Frey et al., 1993 https://doi.org/10.1126/science.8389057 ) and presynaptic cGMP facilitates synaptic transmission in the striatum (Fieblinger et al., 2022 https://doi.org/10.15252/embr.202154361). Cyclic nucleotide signaling is regulated by phosphodiesterases (PDEs), which can specifically degrade either cAMP, cGMP or both. Using electrophysiology and pharmacology in acute slices, we were able to show that the effects of PDE inhibition differed greatly in the hippocampus and the striatum depending on the family of PDEs. In the striatum, inhibiting PDE1 increases transmitter release and chelating presynaptic cGMP prevents potentiation of striatal synapses and decreases motor learning (Fieblinger et al., 2022). In the hippocampus, PDE1 inhibition also increases synaptic transmission in CA1 however this is not due to presynaptic cGMP, pointing to an alternative mechanism that is yet to be elucidated. Furthermore, in contrast to the increase in synaptic transmission by inhibitors of PDE1 in both striatum and hippocampus, PDE10A inhibition decreases synaptic strength only in the hippocampus. Further experiments will focus on elucidating how different PDEs affect synaptic transmission in the hippocampus with a focus on the dual specificity PDEs.