Noradrenergic stabilization of heterosynaptic LTP requires activation of Epac in the hippocampus

Abstract

Beta-adrenergic receptor (β-AR) activation by norepinephrine (NE) enhances memory and stabilizes long-term potentiation (LTP), a form of synaptic plasticity believed to underlie some forms of hippocampal memory. LTP can occur at multiple synaptic pathways as a result of strong stimulation to one pathway preceding milder stimulation of an adjacent, independent pathway. Synaptic tagging allows LTP to be transferred, or captured, at heterosynaptic pathways. Previous research has shown that β-AR activation promotes heterosynaptic LTP by engaging various signaling cascades. In particular, cyclic adenosine monophosphate (cAMP) activates cAMP-dependent protein kinase A (PKA) and guanine nucleotide exchange protein activated by cAMP (Epac), to enhance LTP. Epac activation can occlude subsequent induction of stable homosynaptic LTP after β-AR activation, but it is unclear whether Epac activation is required for heterosynaptic LTP following pairing of the natural transmitter, NE, with one 100 Hz train of stimulation ("NE-LTP"). Using electrophysiologic recordings of CA1 field excitatory postsynaptic potentials during stimulation of two independent synaptic pathways in murine hippocampal slices, we show that distinct inhibitors of Epac blocked stabilization of homo-and heterosynaptic NE-LTP. PKA inhibition also attenuated heterosynaptic transfer of NE-LTP, but only when a PKA inhibitor was applied during tetanization of a second, heterosynaptic pathway that was not treated with NE. Our data suggest that NE, paired with 100 Hz, activates Epac to stabilize homo-and heterosynaptic LTP. Epac may regulate the production of plasticity-related proteins and subsequent synaptic capture of NE-LTP at a heterosynaptic pathway. Epac activation under these conditions may enable behavioral experiences that engage noradrenergic inputs to hippocampal circuits to be transformed into stable long-term memories.

Norepinephrine stabilizes translation‐dependent, homosynaptic long‐term potentiation through mechanisms requiring the cAMP sensor Epac, mTOR and MAPK

“…A requirement for Epac selectively during HFS-induced stimulation corroborates previous results demonstrating that direct activation of Epac boosts the magnitude and duration of LTP within CA1 (Brandwein & Nguyen, 2019;Gelinas, Banko, et al, 2008). These results complement previous findings demonstrating that β-ARs stabilize divergent synaptic inputs through a mechanism requiring Epac signalling during heterosynaptic LTP (Brandwein & Nguyen, 2019). Recruitment of Epac during pairing of HFS with NE may simulate formation of memory with high salience, thereby triggering immediate encoding (Richlitzki, Latour, & Schwarzel, 2017).…”

“…This form of homosynaptic LTP appears to require translation-dependent processes and signalling molecules linked to regulation of protein synthesis, including mTOR and MAPK. These data establish that, similar to heterosynaptic protocols (Brandwein & Nguyen, 2019), activation of noradrenergic receptors with NE may recruit multiple signalling cascades including those coupling to Epac, which could converge on translation regulation to govern enduring changes in synaptic strength in the hippocampus.…”

“…Based on this observation, the possibility remains that Epac inhibition compromises NMDA receptor modulation independently or downstream of noradrenergic receptor activation, thereby attenuating LTP induction as opposed to maintenance. However, other studies have successfully tested the role of Epac in different forms of synaptic plasticity using these inhibitors (Brandwein & Nguyen, 2019; Whitaker & Wei, 2009) and NMDAR currents were intact following genetic deletion of Epac1 and Epac2, although LTP was still impaired (Yang et al., 2012). Attenuated LTP induction may also be the result of shunted neuronal excitability normally associated with NE application which would limit spike discharge rates during high‐frequency tetanus.…”

“…An alternative route through which cAMP couples to downstream effectors is through Epac (Holz, Kang, Harbeck, Roe, & Chepurny, 2006), which has been implicated in β-AR-dependent LTP- (Gelinas, Banko, et al, 2008) and NEinduced heterosynaptic LTP (Brandwein & Nguyen, 2019). To determine if Epac signalling is required for NE-induced homosynaptic LTP, the Epac signalling inhibitor brefeldin A (BFA, 50 µM) was co-applied with NE, resulting in a complete block of NE-LTP ( Figure 2c; mean fEPSPs were 102 ± 5% of baseline).…”

“…An alternative pathway through which norepinephrine may modulate synaptic plasticity is through initiation of exchange protein directly activated by cAMP (Epac) signalling. Direct pharmacological activation of Epac prolongs LTP (Gelinas, Banko, et al, 2008), and preliminary evidence using a heterosynaptic protocol suggests that norepinephrine may similarly recruit Epac during synaptic plasticity (Brandwein & Nguyen, 2019).…”