Mutation of the α_2A-Adrenoceptor Impairs Working Memory Performance and Annuls Cognitive Enhancement by Guanfacine

“…The present results do not indicate the nature of the neural mechanism underlying enhanced working memory, but such an effect could potentially be a result of increased firing by neurons in the locus coeruleus, which would lead to a phasic increase in norepinephrine release throughout the cortex (Aston-Jones Krebs et al, 2018;Murphy et al, 2011;Nieuwenhuis et al, 2005). This is consistent with prior findings that norepinephrine is critical for signaling oddballs in humans and that norepinephrine depletion leads to working memory deficits in nonhuman primates (Arnsten, 2006;Arnsten & Goldman-Rakic, 1985;Brozoski et al, 1979;Cai et al, 1993;Franowicz et al, 2002;Strange & Dolan, 2007;Zhang et al, 2013). More generally, the enhanced working memory we observed for oddballs could reflect greater allocation of attention to rare stimuli.…”

“…The present results do not indicate the nature of the neural mechanism underlying enhanced working memory, but such an effect could potentially be a result of increased firing by neurons in the locus coeruleus, which would lead to a phasic increase in norepinephrine release throughout the cortex (Aston-Jones and Cohen 2005; Krebs et al 2018;Murphy et al 2011;Nieuwenhuis et al 2005). This is consistent with prior findings that norepinephrine is critical for signaling oddballs in humans and that norepinephrine depletion leads to working memory deficits in nonhuman primates (Arnsten 2006;Arnsten and Goldman-Rakic 1985;Brozoski et al 1979;Cai et al 1993;Franowicz et al 2002;Strange and Dolan 2007;Zhang et al 2013). More generally, the enhanced working memory we observed for oddballs could reflect greater allocation of attention to rare stimuli.…”

“…In the present study, the molecular analysis of PI3Kc KO mice revealed a main mechanism, involving LC-NA system leading to an increased NA transmission in fronto-striatal structures, predominantly regulated by NA neurons, able to exert an inhibitory control over DA transmission. This neurobiological perspective fits very well with the current neuropsychological, genetic, imaging and pharmacological data emerging in ADHD research, providing compelling support for a noradrenergic hypothesis of ADHD and demonstrating that very high levels of catecholamine release disrupt cognitive functions of the PFC (Arnsten & Goldman-Rakic, 1985;Franowicz et al, 2002). Our findings show that this mechanism is mediated by the constitutive presence of PI3Kc in the LC where, through a kinase-independent mechanism, it controls PDE4D activity to keep homeostatic levels of cAMP.…”