L-type Ca2+ channels and charybdotoxin-sensitive Ca2+-activated K+ channels are required for reduction of GABAergic activity induced by ß2-adrenoceptor in the prefrontal cortex.

Whereas ß2-adrenoceptor (ß2-AR) has been reported to reduce GABAergic activity in the prefrontal cortex (PFC), the underlying cellular and molecular mechanisms have not been completely determined. Here, we showed that ß2-AR agonist Clenbuterol (Clen) decreased GABAergic transmission onto PFC layer V/VI pyramidal neurons via a presynaptic mechanism without altering postsynaptic GABA receptors. Clen decreased the action potential firing rate but increased the burst afterhyperpolarization (AHP) amplitude in PFC interneurons. Application of L-type Ca2+ channel or charybdotoxin-sensitive Ca2+-activated K+ channel inhibitors blocked Clen-induced decreases in action potential firing rate, spontaneous inhibitory postsynaptic current (sIPSC) frequency and Clen-induced enhancement of AHP amplitude, suggesting that the effects of Clen involves L-type Ca2+ Channels and charybdotoxin-sensitive Ca2+-activated K+ channels. Our results provide a potential cellular mechanism by which Clen controls GABAergic neuronal activity in PFC.

Prelimbic cortex extracellular signal-regulated kinase 1/2 activation is required for memory retrieval of long-term inhibitory avoidance.

Neural mechanism underlying memory retrieval has been extensively studied in the hippocampus and amygdala. However, little is known about the role of medial prefrontal cortex in long-term memory retrieval. We evaluate this issue in one-trial step-through inhibitory avoidance (IA) paradigm. Our results showed that, 1) inactivation of mPFC by local infusion of GABAA-receptor agonist muscimol caused severe deficits in retrieval of 1-day and 7-day but had no effects on 2-h inhibitory avoidance memory; 2) the protein level of phosphorylated-ERK1/2 in mPFC were significantly increased following retrieval of 1-day and 7-day IA memory, so did the numbers of phosphorylated-ERK (pERK) and phosphorylated-CREB (pCREB) labeled neurons; 3) intra-mPFC infusion of ERK kinase inhibitor PD98095 significantly reduced phosphorylated ERK1/2 levels and phosphorylated-ERK1/2 and phosphorylated-CREB labeled cells, and severely impaired retrieval of 7-day IA memory when the drugs were administrated 30min prior to test. The present study provides evidence that retrieval of long-lasting memory for inhibitory avoidance requires mPFC and involves the ERK-CREB signaling cascade.

Phenylephrine enhances glutamate release in the medial prefrontal cortex through interaction with N-type Ca2+ channels and release machinery.

α1 -adrenoceptors (α1 -ARs) stimulation has been found to enhance excitatory processes in many brain regions. A recent study in our laboratory showed that α1 -ARs stimulation enhances glutamatergic transmission via both pre- and post-synaptic mechanisms in layer V/VI pyramidal cells of the rat medial prefrontal cortex (mPFC). However, a number of pre-synaptic mechanisms may contribute to α1 -ARs-induced enhancement of glutamate release. In this study, we blocked the possible post-synaptic action mediated by α1 -ARs to investigate how α1 -ARs activation regulates pre-synaptic glutamate release in layer V/VI pyramidal neurons of mPFC. We found that the α1 -ARs agonist phenylephrine (Phe) induced a significant enhancement of glutamatergic transmission. The Phe-induced potentiation was mediated by enhancing pre-synaptic glutamate release probability and increasing the number of release vesicles via a protein kinase C-dependent pathway. The mechanisms of Phe-induced potentiation included interaction with both glutamate release machinery and N-type Ca(2+) channels, probably via a pre-synaptic Gq /phospholipase C/protein kinase C pathway. Our results may provide a cellular and molecular mechanism that helps explain α1 -ARs-mediated influence on PFC cognitive functions. Alpha1 -adrenoceptor (α1 -ARs) stimulation has been reported to enhance glutamatergic transmission in layer V/VI pyramidal neurons of the rat medial prefrontal cortex (mPFC). We found that α1 -ARs agonist phenylephrine (Phe) increases pre-synaptic glutamate release probability and the number of released vesicles via interaction with both glutamate release machinery and N-type Ca(2+) channels. Our results may provide a cellular and molecular mechanism that helps explain α1 -ARs-mediated influence on PFC cognitive functions. Gq, Gq protein; PLC, phospholipase C; PKC, protein kinase C; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA, N-methyl-d-aspartate; Glu, glutamate; Phe, phenylephrine.