Dysregulation of cAMP-PKA-mediated mechanisms disrupts basal synaptic function in the absence of presynaptic FMRP

Abstract The regulation of presynaptic mechanisms by the fragile X messenger ribonucleoprotein (FMRP) remains incompletely understood despite their potential importance to synaptic dysfunction reported in Fragile X syndrome. We combined post-developmental, cell-specific deletion of FMRP in dentate granule cells of the hippocampus with optogenetics, whole-cell patch-clamp electrophysiology and super resolution imaging. The selective loss of FMRP in DG cells did not alter their intrinsic excitability. The amplitude of synaptic currents was reduced at the output mossy fiber synapses in the absence of presynaptic FMRP, whereas short-term facilitation remained intact. We demonstrate that basal synaptic activity is regulated by PKA at mature mossy fiber synapses, and our results indicate alterations in cAMP-PKA signaling and a potential reduction in the readily releasable pool size in mossy fiber boutons lacking FMRP. Presynaptic FMRP is therefore required for efficient basal neurotransmission at mature mossy fiber synapses and likely acts through cAMP-PKA-dependent signaling pathway. Significance statement The fragile X messenger ribonucleoprotein (FMRP) has been extensively studied as a regulator of postsynaptic mechanisms. However, its physiological functions in presynaptic terminals remain incompletely understood. Using post-developmental, cell-specific deletion of FMRP, we show that presynaptic FMRP is required to maintain efficient basal neurotransmission at hippocampal mossy fiber synapses and identify cAMP-PKA signaling as a potential mechanism for this effect. Taken together, these results highlight a physiological role for presynaptic FMRP during basal synaptic activity and demonstrate how time-controlled gene-editing approaches via viral infection can distinguish primary molecular functions from developmental compensations, thereby shedding new light on both the presynaptic function of FMRP and the pathophysiology of Fragile X syndrome. Highlights Presynaptic loss of FMRP reduces basal synaptic activity at hippocampal Mf synapses. Basal synaptic activity is regulated by PKA in adult Mf synapses. AC-cAMP-PKA pathway is impaired during basal synaptic activity in the absence of presynaptic FMRP. RRP size is very likely reduced in AZs at Mf terminals.