Differential effects of PDE4A5 on cAMP-dependent forms of long-term potentiation

Abstract

AbstractcAMP signaling is critical for memory consolidation and certain of forms long-term potentiation (LTP). Phosphodiesterases (PDEs), enzymes that degrade the second messenger cAMP and cGMP, are highly conserved during evolution and represent a unique set of drug targets, given the involvement of these enzymes in several pathophysiological states including brain disorders. The PDE4 family of cAMP selective PDEs, exert regulatory roles in memory and synaptic plasticity, but the specific roles of distinct PDE4 isoforms in these processes are poorly understood. Building on our previous work demonstrating that spatial and contextual memory deficits were caused by expressing selectively the long isoform of the PDE4A subfamily, PDE4A5, in hippocampal excitatory neurons, we now investigate the effects of PDE4A isoforms on different cAMP-dependent forms of LTP. We find that PDE4A5 impairs long-lasting LTP induced by theta burst stimulation (TBS) while sparing long-lasting LTP induced by spaced 4-train stimulation (4X100Hz). This effect requires the unique N-terminus of PDE4A5 and is specific to this long isoform. Targeted overexpression of PDE4A5 in area CA1 is sufficient to impair TBS-LTP, suggesting that cAMP levels in the postsynaptic neuron are critical for TBS-LTP. Our results shed light on the inherent differences among the PDE4A subfamily isoforms, emphasizing the importance of the long isoforms, which have a unique N-terminal region. Advancing our understanding of the function of specific PDE isoforms will pave the way for developing isoform-selective approaches to treat the cognitive deficits that are debilitating aspects of psychiatric, neurodevelopmental, and neurodegenerative disorders.Key PointsHippocampal overexpression of a PDE4A subfamily long isoform, PDE4A5, but not a short isoform PDE4A1, impairs spatial and contextual fear memory and the N-terminus of PDE4A5 is important for this effect.Hippocampal overexpression of PDE4A isoforms, PDE4A1 and PDE4A5 do not impair LTP induced by spaced tetanic stimulation at the CA3-CA1 synapses.Hippocampal overexpression of PDE4A5, but not PDE4A1 or the N-terminus truncated PDE4A5 (PDE4A5Δ4) selectively impairs LTP induced by theta burst stimulation (TBS) at the CA3-CA1 synapses and expression of PDE4A5 in area CA1 is sufficient for the TBS-LTP deficit.These results suggest that PDE4A5, through its N-terminus, regulates cAMP pools that are critical for memory consolidation and expression of TBS-LTP at the CA3-CA1 synapses.GRAPHICAL ABSTRACTSpaced tetanic stimulation and TBS induce cAMP synthesis and activation of PKA to promote signaling cascades that facilitate expression of long-lasting LTP at the CA3-CA1 synapses. PDE4A5 overexpression in the hippocampus selectively impairs cAMP and PKA dependent TBS-LTP at the CA3-CA1 synapses, while sparing LTP induced by spaced tetanization.