α₂‐Noradrenergic receptors activation enhances excitability and synaptic integration in rat prefrontal cortex pyramidal neurons via inhibition of HCN currents

Abstract

Stimulation of α 2 -noradrenergic (NA) receptors within the PFC improves working memory performance. This improvement is accompanied by a selective increase in the activity of PFC neurons during delay periods, although the cellular mechanisms responsible for this enhanced response are largely unknown. Here we used current and voltage clamp recordings to characterize the response of layer V-VI PFC pyramidal neurons to α 2 -NA receptor stimulation. α 2 -NA receptor activation produced a small hyperpolarization of the resting membrane potential, which was accompanied by an increase in input resistance and evoked firing. Voltage clamp analysis demonstrated that α 2 -NA receptor stimulation inhibited a caesium and ZD7288-sensitive hyperpolarization-activated (HCN) inward current. Suppression of HCN current by α 2 -NA stimulation was not dependent on adenylate cyclase but instead required activation of a PLC-PKC linked signalling pathway. Similar to direct blockade of HCN channels, α 2 -NA receptor stimulation produced a significant enhancement in temporal summation during trains of distally evoked EPSPs. These dual effects of α 2 -NA receptor stimulation -membrane hyperpolarization and enhanced temporal integration -together produce an increase in the overall gain of the response of PFC pyramidal neurons to excitatory synaptic input. The net effect is the suppression of isolated excitatory inputs while enhancing the response to a coherent burst of synaptic activity.

HCN channels: Structure, cellular regulation and physiological function

“…An alternative modulation of HCN channels by a 2 -adrenoceptors in prefrontal neurons has been proposed by a different group [156]. Carr et al suggest that a 2 -adrenoceptor activation suppresses HCN channels in prefrontal neurons through a signalling pathway that does not appear to involve cAMP, but appears to be mediated by PLC-PKC signalling.…”

Hyperpolarization-Activated Cation Channels: From Genes to Function

“…Carr et al (71) suggested that ␣ 2 -adrenoceptor activation suppresses HCN channels in prefrontal neurons through a cAMP-independent signaling pathway that appears to be mediated by PLC-PKC signaling.…”

Subunit-Specific Effects of Isoflurane on Neuronal Ih in HCN1 Knockout Mice

“…The combination of synaptic enhancement (via effects on dendritic I h ) with membrane hyperpolarization (via effects on somatic I h ) provides a background in which isolated synaptic inputs are less effective, whereas effects of synchronous excitatory synaptic potentials are enhanced. In general, this situation would favor coherent oscillatory behavior (Carr et al 2007) and, indeed, decreases in I h have been observed in a number of epilepsy models in rodents (Jung et al 2007;Kole et al 2007;Shah et al 2004).…”