Differential regulation of synaptic transmission by adrenergic agonists via protein kinase A and protein kinase C in layer V pyramidal neurons of rat cerebral cortex

Activation of α1- and β-adrenoceptors modulates excitatory neural transmission in the cerebral cortex in opposite manners. Our in vitro optical imaging study using a voltage sensitive dye has revealed that an α1-adrenoceptor agonist, phenylephrine, suppresses the excitatory propagation evoked by stimulation of the white matter, whereas a β-adrenoceptor agonist, isoproterenol, tends to potentiate the excitatory propagation especially in the deeper layers. The present study aimed to explore what kind of second messengers are involved in noradrenergic modulation of synaptic transmission by using intracellular recording in rat cerebrocortical slice preparation. Evoked excitatory postsynaptic potentials (eEPSPs) were recorded from regular spiking and bursting pyramidal neurons in layer V, which generate single and complex action potentials in response to a short (5 ms) depolarizing current pulse injection, respectively. Application of phenylephrine attenuated eEPSPs, and prazosin, an α1-adrenoceptor antagonist, precluded the phenylephrine-induced suppression of eEPSPs. The EPSPs suppression by phenylephrine was blocked by pre-application of a protein kinase C (PKC) inhibitor, chelerythrine, whereas a PKC activator, phorbol 12-myristate 13-acetate (phorbol ester), mimicked the effect of phenylephrine. On the other hand, application of isoproterenol enhanced eEPSPs, and propranolol, a β-adrenoceptor antagonist, precluded the excitatory effect of isoproterenol on eEPSPs. The membrane permeant analog of cyclic-3′,5′-AMP (cAMP), N6,2′-O-dibutyryl-AMP (db-cAMP), mimicked the facilitatory effect of isoproterenol. Isoproterenol-induced enhancement of eEPSPs was promoted by pre-application of 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidinone (Ro 20–1724), a cAMP-specific phosphodiesterase inhibitor. A selective protein kinase A inhibitor, N-[2-(p-bromocinnamylamino)ethyl]-5-soquinolinesulfonamide (H-89), inhibited the excitatory effect by isoproterenol. There was no significant difference in the effects of adrenergic agonists/antagonists and protein kinase activators/inhibitors between regular spiking and bursting neurons in layer V. Thus, it is likely that the suppressive effect on eEPSPs by activation of α1-adrenoceptors was mediated by protein kinase C, and excitatory effect by activation of β-adrenoceptors was mediated by cAMP/protein kinase A cascade in layer V pyramidal neurons.