Learning-related postburst afterhyperpolarization reduction in CA1 pyramidal neurons is mediated by protein kinase A

Abstract

Learning-related reductions of the postburst afterhyperpolarization (AHP) in hippocampal pyramidal neurons have been shown ex vivo, after trace eyeblink conditioning. The AHP is also reduced by many neuromodulators, such as norepinephrine, via activation of protein kinases. Trace eyeblink conditioning, like other hippocampus-dependent tasks, relies on protein synthesis for consolidating the learned memory. Protein kinase A (PKA) has been shown to be a key contributor for protein synthesis via the cAMP-response element-binding pathway. Here, we have explored a potential involvement of PKA and protein kinase C (PKC) in maintaining the learning-related postburst AHP reduction observed in CA1 pyramidal neurons. Bath application of isoproterenol (1 M), a ␤-adrenergic agonist that activates PKA, significantly reduced the AHP in CA1 neurons from control animals, but not from rats that learned. This occlusion suggests that PKA activity is involved in maintaining the AHP reduction measured ex vivo after successful learning. In contrast, bath application of the PKC activator, (-) indolactam V (0.2 M), significantly reduced the AHP in CA1 neurons from both control and trained rats, indicating that PKC activity is not involved in maintaining the AHP reduction at this point after learning.hippocampus ͉ protein kinase C ͉ trace eyeblink T he postburst afterhyperpolarization (AHP) has been repeatedly demonstrated ex vivo to be reduced in hippocampal pyramidal neurons after hippocampus-dependent learning, such as the trace eyeblink conditioning (EBC) task (1). Trace EBC is a hippocampus-dependent task (2-4) that, like others (5, 6), requires protein synthesis for learning and consolidation of the memory (7), yet the molecular cascade that underlies this learning-related AHP alteration after trace EBC has not been studied or identified.The postburst AHP is predominantly a Ca 2ϩ -dependent K ϩ current with 2 distinct components (8-10). The SK2 channels underlie the apamin-sensitive medium AHP (11-13) and have been shown to be intimately involved in regulating synaptic plasticity in dendritic spines along with NMDA receptors (14). The channel underlying the later, slow AHP has yet to be discovered; however, it is thought to be localized to the apical and basal dendrites in close proximity to the soma (15, 16). Because of its somatic localization, the slow AHP may play a significant role in the final somatic integration of synaptic inputs. Unless specified, we will be referring to both the medium and slow components of the AHP throughout the text. Activation of protein kinases via various neuromodulators reduces the AHP (10, 17). Specifically, activation of cholinergic and metabotropic glutamate receptors have been shown to reduce the AHP via protein kinase C (PKC) and Ca 2ϩ /calmodulin-dependent protein kinase II (CaMKII) (18)(19)(20)(21)(22). Activation of monoamine receptors reduces the AHP via protein kinase A (PKA) (21, 23). In addition to reducing the AHP, all 3 kinases have been implicated in long-term potentiation (LTP), wi...

Learning‐dependent plasticity of hippocampal CA1 pyramidal neuron postburst afterhyperpolarizations and increased excitability after inhibitory avoidance learning depend upon basolateral amygdala inputs

“…Learning-dependent reductions in mAHP and sAHP have been reported in hippocampus following acquisition of trace eyeblink conditioning (Matthews et al, 2009). In addition, NE has been shown to reduce both currents via PKA-dependent phosphorylation (Pedarzani and Storm, 1995;Lancaster et al, 2006;Oh et al, 2009). Learning-dependent AHP plasticity in multitrial tasks has been shown to be PKA-but not PKC-dependent (Oh et al, 2009).…”

“…In addition, NE has been shown to reduce both currents via PKA-dependent phosphorylation (Pedarzani and Storm, 1995;Lancaster et al, 2006;Oh et al, 2009). Learning-dependent AHP plasticity in multitrial tasks has been shown to be PKA-but not PKC-dependent (Oh et al, 2009). Learning-dependent AHP plasticity occurred with different time courses in dorsal and ventral CA1.…”

Unraveling the Time Domains of Corticosteroid Hormone Influences on Brain Activity: Rapid, Slow, and Chronic Modes

“…This has been shown in detail with regard to serotonin (see, for example, Joëls et al, 1991;Laaris et al, 1999;Fairchild et al, 2003; for reviews, see Joëls et al, 2007;Haj-Dahmane and Shen, 2011), noradrenaline, and, to a lesser extent, CRH (Gallagher et al, 2008). For instance, noradrenaline (acting via ␤-receptors) targets the AHP (Madison and Nicoll, 1982;Faber and Sah, 2005;Oh et al, 2009), GluA2 subunit trafficking (Liu et al, 2010), and (maintenance of) LTP (Thomas et al, 1996;Straube and Frey, 2003;Gelinas and Nguyen, 2005), thereby mimicking effects described for corticosteroids. These common endpoints form potential platforms for interaction between various stress mediators .…”

The roles of protein kinases in learning and memory

“…The first PKA wave occurs immediately after training and the second after 3-6 h. Both waves of PKA activity might be important to induce CREB-mediated gene transcription (Ahi et al 2004;Sindreu et al 2007). Next to regulating gene transcription for LTM formation, PKA has also been implicated in synaptic tagging (Young et al 2006;Moncada et al 2011) and long-term reduction of the slow afterhyperpolarization (AHP), which regulates neuronal firing (Oh et al 2009). Further, PKA activity is required for the behavioral counterpart of synaptic tagging (Moncada et al 2011).…”