Effects Of Monoamine Neurotransmitters On Presynaptic Transmission And Excitability In Prefrontal Cortex And Its Intracellular Mechanism

Part I. Intracellular Mechanisms Underlying a2A-Adrenergic Suppression of Prefrontal Cortical Excitatory Synaptic Transmission in RatsStimulation of αC2A-adrenoceptors (ARs) in the prefrontal cortex (PFC) produces a beneficial effect on cognitive functions such as working memory. The α2A-adrenergic agonist guanfacine has been used experimentally and clinically for treatment of psychiatric disorders such as attention-deficit/hyperactivity disorder (ADHD). A previous study in our laboratory showed that stimulation of α2A-AR suppresses excitatory synaptic transmission in the medial prefrontal cortex (mPFC) of rat. However, the intracellular mechanism remains unclear. In the present study, we recorded evoked excitatory postsynaptic current (eEPSC) in layer V-VI pyramidal cells of rat mPFC, using whole-cell patch-clamp recording technique. Our results show that α2A-AR inhibition of excitatory synaptic transmission in mPFC pyramidal cells is mediated via Gi-cAMP-PKA-PP1and/or Gi-cAMP-PKA-PP1-CaMKII signaling pathways. Part Ⅱ. Dopaminergic Modulation of Post-burst Afterhyperpolarization in Rat Prefrontal Cortical Pyramidal NeuronsDopamine (DA) receptors in the prefrontal cortex (PFC) modulate neuronal plasticity and persistent spike firing activity that may contribute to cognitive functions such as working memory. An understanding of the ionic bases of DA actions that mediate an increase in firing of PFC pyramidal neurons is still incomplete. Using whole-cell patch-clamp recordings in layer Ⅴ-Ⅵ pyramidal neurons in the prefrontal cortex we replicated that previous findings of a DA modulation of PFC neuronal excitability beingvia D1/5but not D2/3/4receptors. Post-spike burst hyperpolarization (AHP) may be one mechanism that DA modulate to enhance evoked spike firing. We found that DA via D1/5receptor activationsuppressed AHP while augmenting adepolarization afterpotential (DAP) following the post-burst AHP may be responsible for the enhancement of neuronal excitability. This modulation of the post-burst AHP amplitude by DA D1/5receptor activation is via regulating a calcium-dependent and apamin-sensitive K+channel, but not via regulating a HCN channels. The DA modulation of the post-burst AHP time constant resulted in the summation of the reduced calcium/apamin-sensitive AHP and led indirectly to augment DAP that follows the post-burst AHP. Together, these D1-dependent mechanisms may contribute to the persistent repetitive firing of the pyramidal neurons.during working memory processing.