The objective of this study was to evaluate the role of β-adrenergic receptors in modulating associative long-term potentiation (LTP) induced at CA1 synapses. Two independent Schaffer collateral pathways were stimulated in hippocampal slices. The field EPSP (fEPSP) response evoked in one pathway (the weak pathway) was small, whereas a large response, usually 80–90% of the maximum, was evoked in the strong pathway. After recording of the baseline fEPSP evoked at 0.033 Hz, LTP of the weak pathway could be associatively induced by paired stimulation of the weak and strong pathways 100 times at 6 sec intervals, with stimulation of the weak pathway preceded 3–10 msec. However, pairing protocols with an interval between stimulation of the two pathways >10 msec resulted in no LTP. The induced LTP was NMDA receptor dependent, because 50μm d,l-APV blocked its induction. Bath application of 1μmisoproterenol enhanced LTP by increasing the window of the stimulation interval up to 15 msec but did not affect the magnitude of the LTP induced by pairing protocols with intervals <10 msec. Similar results were obtained when the experiments were repeated using whole-cell recording. These results suggest that activation of β-adrenergic receptors can enhance associative LTP by increasing the width of the time window rather than the magnitude of the LTP. Enhancement of LTP by β-adrenergic receptors was blocked in slices by pretreatment with inhibitors of protein kinase A or mitogen-activated protein kinase, suggesting that these signaling cascades are involved in this process.

Exogenous application of agonists at the kainate subtype of glutamate receptors has been shown to depress evoked monosynaptic inhibition by γ-aminobutyric acid (GABA)ergic interneurons in the hippocampus. This observation has led to the hypothesis that synaptic release of endogenous glutamate might have a disinhibitory effect on neuronal circuits, in addition to depolarizing neurons via postsynaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainate, andN-methyl-d-aspartic acid (NMDA) receptors. It is not known, however, if glutamate released from excitatory neurons has the same kainate receptor-mediated effect on monosynaptic inhibitory transmission as exogenous agonist application. Indeed, the recent demonstration that excitatory synaptic signals elicited in interneurons are partly mediated by kainate receptors suggests that these receptors may have a pro- rather than disinhibitory role. Here, we examine the effect of synaptically released glutamate on monosynaptic inhibitory signaling. In the presence of antagonists to AMPA and NMDA receptors, brief bursts of activity in glutamatergic afferent fibers reduce GABAergic transmission. This depression of inhibition is reversibly abolished by blocking kainate receptors. It persists when GABA_Breceptors are blocked and is enhanced by blocking metabotropic glutamate receptors, possibly explained by presynaptic regulation of glutamate release from excitatory afferents by metabotropic autoreceptors. We conclude that the net kainate receptor-mediated effect of synaptically released glutamate is to reduce monosynaptic inhibition. Since this form of disinhibition may contribute to seizure initiation, kainate receptors may constitute an important target for anticonvulsant drug development.

Application of phorbol 12,13-diacetate (PDA) caused marked enhancement of synaptic transmission of nociceptive parabrachio-amygdaloid (PBA) input onto neurons of the capsular central amygdaloid (CeAC) nucleus. The potentiation of PBA–CeAC EPSCs by PDA involved a presynaptic protein kinase C (PKC)-dependent component and a postsynaptic PKC–extracellular-regulated kinase (ERK)-dependent component. NMDA glutamatergic receptor (NMDAR)-dependent long-term potentiation (LTP) of PBA–CeAC EPSCs, which was also dependent on the PKC–ERK signaling pathway, was induced by tetanus stimulation at 100 Hz. In slices from mice subjected to acid-induced muscle pain (AIMP), phosphorylated ERK levels in the CeAC increased, and PBA–CeAC synaptic transmission was postsynaptically enhanced. The enhanced PBA–CeAC synaptic transmission in AIMP mice shared common mechanisms with the postsynaptic potentiation effect of PDA and induction of NMDAR-dependent LTP by high-frequency stimulation in normal slices, both of which required ERK activation. Since the CeAC plays an important role in the emotionality of pain, enhanced synaptic function of nociceptive (PBA) inputs onto CeAC neurons might partially account for the supraspinal mechanisms underlying central sensitization.