β-Adrenergic Receptors/Epac Signaling Increases the Size of the Readily Releasable Pool of Synaptic Vesicles Required for Parallel Fiber LTP

Abstract

The second messenger cAMP is an important determinant of synaptic plasticity that is associated with enhanced neurotransmitter release. Long-term potentiation (LTP) at parallel fiber (PF)-Purkinje cell (PC) synapses depends on a Ca 21 -induced increase in presynaptic cAMP that is mediated by Ca 21 -sensitive adenylyl cyclases. However, the upstream signaling and the downstream targets of cAMP involved in these events remain poorly understood. It is unclear whether cAMP generated by b-adrenergic receptors (bARs) is required for PF-PC LTP, although noradrenergic varicosities are apposed in PF-PC contacts. Guanine nucleotide exchange proteins directly activated by cAMP [Epac proteins (Epac 1-2)] are alternative cAMP targets to protein kinase A (PKA) and Epac2 is abundant in the cerebellum. However, whether Epac proteins participate in PF-PC LTP is not known. Immunoelectron microscopy demonstrated that bARs are expressed in PF boutons. Moreover, activation of these receptors through their agonist isoproterenol potentiated synaptic transmission in cerebellar slices from mice of either sex, an effect that was insensitive to the PKA inhibitors (H-89, KT270) but that was blocked by the Epac inhibitor ESI 05. Interestingly, prior activation of these bARs occluded PF-PC LTP, while the b1AR antagonist metoprolol blocked PF-PC LTP, which was also absent in Epac2 2/2 mice. PF-PC LTP is associated with an increase in the size of the readily releasable pool (RRP) of synaptic vesicles, consistent with the isoproterenolinduced increase in vesicle docking in cerebellar slices. Thus, the bAR-mediated modulation of the release machinery and the subsequent increase in the size of the RRP contributes to PF-PC LTP.

Celsr3 is required for Purkinje cell maturation and regulates cerebellar postsynaptic plasticity

“…Multiple intracellular molecules are involved in the process, such as protein phosphatases (PP1, PP2A, and PP2B), T-type Ca 2+ channels, and nitric oxide (Gutierrez-Castellanos, et al, 2017;Belmeguenai and Hansel, 2005;Kakegawa and Yuzaki, 2005;Lev-Ram, et al, 2002). Recent studies show that cAMP signaling activates the GluA2/GluA3-dependent AMPARs by enhancing their conductance, which induces LTP (Martin, et al, 2020;Gutierrez-Castellanos, et al, 2017). In our study, the cAMP agonist forskolin was equally efficient in inducing LTP in control and Celsr3 cKO slices.…”

“…The second messenger cyclic adenosine monophosphate (cAMP) is a key modulator of the PF-PC postsynaptic LTP, which is triggered by G-protein-coupled postsynaptic receptors such as adrenergic receptors (Martin, et al, 2020). To test whether cAMP activation induces LTP in PCs, the cAMP agonist forskolin was perfused in cerebellar slices during baseline recording of PCs.…”

“…Both postsynaptic long-term potentiation (LTP) and long-term depression (LTD) occur at PF-PC synapses, and are induced by a low-frequency 1 Hz stimulation of PFs (LTP) and both PFs-CFs (LTD) (Hoxha, et al, 2016;Hirano, 2013;Sakurai, 1987;Ito, et al, 1982). LTP and LTD implicate a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs), which are recruited (LTP) or internalized (LTD) in PC dendritic spines, generating different intracellular signals (Martin, et al, 2020;Gutierrez-Castellanos, et al, 2017). LTP and LTD can occur in vivo and may play different roles in motor learning: LTP is responsible for the gain-decrease vestibulo-ocular reflex (VOR) adaptation, whereas LTD mediates gain-increase VOR adaptation (Boyden and Raymond, 2003).…”

Stress-Induced Enhanced Long-Term Potentiation and Reduced Threshold for N-Methyl-D-Aspartate Receptor- and β-Adrenergic Receptor-Mediated Synaptic Plasticity in Rodent Ventral Subiculum

“…Albeit direct anatomical evidence of β-ARs in presynaptic terminals of glutamatergic CA1-subiculum synapses is still missing, transport of β-ARs from the soma of CA1 pyramidal cells (Hillman et al, 2005;Guo and Li, 2007) to presynaptic sites is possible. Interestingly, β-AR signaling via direct activation of the guanine nucleotide exchange protein Epac by cAMP is involved in LTP at cerebellar granule cell to Purkinje cell synapses (Martín et al, 2020). There, an increase in the number of synaptic vesicles primed for exocytosis accounts for the potentiation of neurotransmitter release driven by β-ARs.…”

Axonal CB1 receptors mediate inhibitory bouton formation via cAMP increase

“…Epac2 activity can strongly increase synaptic transmission (Fernandes et al, 2015;Gekel and Neher, 2008), yet a role in synapse formation has not been reported. Interestingly, Epac2 was recently found to be downstream of Gs-coupled β adrenergic receptors to mediate presynaptic LTP at parallel fiber synapses to Purkinje cells (Martín et al, 2020). cAMP signaling via PKA, Epac2 or Rho GTPases may affect the axonal cytoskeleton.…”