Signaling mechanism underlying α_2A‐adrenergic suppression of excitatory synaptic transmission in the medial prefrontal cortex of rats

Abstract

Stimulation of α2A‐adrenoceptors (ARs) in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. A previous study in our laboratory showed that α2A‐AR stimulation suppresses excitatory synaptic transmission in layer V‐VI pyramidal cells of the rat medial PFC (mPFC). However, the intracellular mechanism underlying the α2A‐AR suppression remains unclear. In the present study, we recorded evoked excitatory postsynaptic current (eEPSC) in layer V‐VI pyramidal cells of the mPFC, using whole‐cell patch‐clamp recording. We found that the α2A‐AR agonist guanfacine significantly suppresses eEPSC in mPFC pyramidal cells. The α2A‐AR inhibition is mediated by the Gi‐cAMP‐PKA‐PP1‐CaMKII‐AMPAR signaling pathway, as such inhibition no longer exists when each step of this pathway is blocked with NF023, Rp‐cAMP, PKI5–24 or H89, tautomycin, and KN‐62 or KN‐93, respectively.

Norepinephrine versus dopamine and their interaction in modulating synaptic function in the prefrontal cortex

“…Yi and colleagues have shown that the α 2A receptor agonist, guanfacine, significantly suppressed evoked AMPA-EPSCs in PFC pyramidal cells. Overall, the a 2A receptor inhibition is mediated by the G i -cAMP-PKA-PP1-calcium/calmodulin-dependent protein kinase II (CaMKII)-AMPA receptor signaling pathway that can be blocked by different kinase antagonists at different levels (Yi et al, 2013). Conversely, under specific situations such as emotional arousal, NE recruits β receptors to activate the AC-cAMP-PKA-CaMKII pathway, leading to phosphorylation of GluR1 at sites critical for synaptic delivery of AMPARs and memory enhancement (Hu et al, 2007; Tenorio et al, 2010).…”

A computational psychiatry approach identifies how alpha-2A noradrenergic agonist Guanfacine affects feature-based reinforcement learning in the macaque

“…Guanfacine is suggested to exert its positive effects on cognitive functions via these actions on post-synaptic a2A-NAR receptors in the dorsolateral PFC5. Guanfacine is also suggested to suppress glutamatergic synaptic transmission and thereby neural excitability at deeper layers (V/VI) in PFC, potentially governed by similar intra-cellular mechanisms as those controlling HCN channels2122. It has been proposed that at low concentrations, Guanfacine’s actions on HCN channels may predominate, while only at high concentrations glutamate transmission is affected, potentially explaining an inverted-U type function of Guanfacine522.…”

“…Guanfacine is also suggested to suppress glutamatergic synaptic transmission and thereby neural excitability at deeper layers (V/VI) in PFC, potentially governed by similar intra-cellular mechanisms as those controlling HCN channels2122. It has been proposed that at low concentrations, Guanfacine’s actions on HCN channels may predominate, while only at high concentrations glutamate transmission is affected, potentially explaining an inverted-U type function of Guanfacine522. Guanfacine also binds to pre-synaptic alpha 2A receptors on locus coeruleus terminals that act as inhibitory auto-receptors, thereby decreasing NE release23, which may again suggest that high doses of Guanfacine could impair cognitive functions.…”

Targeting Prefrontal Cortical Systems for Drug Development: Potential Therapies for Cognitive Disorders

“…In vitro recordings from layer II/III pyramidal cells in PFC slices found results similar to monkeys, in which α2A-AR stimulation enhances persistent firing via HCN channel closure (81); however, recordings of layer V neurons show reduced presynaptic glutamate release (82, 83), again emphasizing the differences between PFC lamina. Studies in genetically altered mice found that a functional α2A-AR was needed for guanfacine to produce cognitive improvement (84).…”