cAMP/PKA signaling and RIM1alpha mediate presynaptic LTP in the lateral amygdala.

NMDA receptor-dependent long-term potentiation (LTP) of glutamatergic synaptic transmission in sensory pathways from auditory thalamus or cortex to the lateral amygdala (LA) underlies the acquisition of auditory fear conditioning. Whereas the mechanisms of postsynaptic LTP at thalamo-LA synapses are well understood, much less is known about the sequence of events mediating presynaptic NMDA receptor-dependent LTP at cortico-LA synapses. Here, we show that presynaptic cortico-LA LTP can be entirely accounted for by a persistent increase in the vesicular release probability. At the molecular level, we found that signaling via the cAMP/PKA pathway is necessary and sufficient for LTP induction. Moreover, by using mice lacking the active-zone protein and PKA target RIM1alpha (RIM1alpha(-/-)), we demonstrate that RIM1alpha is required for both chemically and synaptically induced presynaptic LTP. Further analysis of cortico-LA synaptic transmission in RIM1alpha(-/-) mice revealed a deficit in Ca(2+)-release coupling leading to a lower baseline release probability. Our results reveal the molecular mechanisms underlying the induction of presynaptic LTP at cortico-LA synapses and indicate that RIM1alpha-dependent LTP may involve changes in Ca(2+)-release coupling.

Short-term regulation of information processing at the corticoaccumbens synapse.

In relation to expectation and delivery of reward, pyramidal neurons of the prefrontal cortex either switch from a single spiking mode to transient phasic bursting, or gradually increase their sustained tonic activity. Here, we examined how switching between firing modes affects information processing at the corticoaccumbens synapse. We report that increasing presynaptic firing frequency in a tonic manner either depresses or facilitates synaptic transmission, depending on initial probability of release. In contrast, repeated bursts of stimulation of cortical afferents trigger a new form of short-term potentiation of synaptic transmission (RB-STP) in the nucleus accumbens (NAc). RB-STP involves the regulation of axonal excitability mediated by 4-AP-sensitive potassium channels in afferent cortical neurons. Thus, in a tonic mode, information flow is tightly controlled by regulatory mechanisms at the level of presynaptic terminals, whereas switching to a bursting mode reliably enhances efficacy of information processing for all cortical afferents to NAc neurons.

Functional characterization of kainate receptors in the mouse nucleus accumbens.

Kainate receptors are abundantly expressed in the nucleus accumbens but their functional characterization and their role in synaptic transmission has not yet been investigated. Using patch-clamp recordings in mouse nucleus accumbens slices, we show the presence of functional kainate receptors activated by low concentrations of kainate (100-300 nM) in medium size neurons. These somatodendritic receptors are comprised of the GluR6 subunit, since they are absent in GluR6-deficient mice. Kainate receptors do not directly participate in glutamatergic synaptic transmission evoked by electrical stimulation of cortical afferent fibers in nucleus accumbens neurons. However, application of low concentrations of kainate inhibits cortico-accumbens synaptic transmission, by increasing synaptic failure rate and increasing variation coefficient, thus indicating a presynaptic site of action. Presynaptic kainate receptors are observed both in GluR6 and in GluR5-deficient mice, but are absent in mice devoid of both subunits. Hence, at variance with somatodendritic kainate receptors, presynaptic kainate receptors on cortical afferents are composed of both GluR5 and GluR6 kainate receptor subunits. These results indicate that different subtypes of kainate receptors, representing distinct pharmacological targets, should play important roles in the synaptic integration properties of nucleus accumbens neurons.

L-type voltage-dependent Ca(2+) channels mediate expression of presynaptic LTP in amygdala.

The molecular mechanisms underlying the expression of postsynaptic long-term potentiation (LTP) at glutamatergic synapses are well understood. However, little is known about those that mediate the expression of presynaptic LTP. We found that presynaptic LTP at cortical inputs to the mouse lateral amygdala was blocked and reversed by L-type voltage-dependent Ca(2+) channel (L-VDCC) blockers. Thus, a persistent increase in L-VDCC-mediated glutamate release underlies the expression of presynaptic LTP in the amygdala.

Spike-dependent intrinsic plasticity increases firing probability in rat striatal neurons in vivo.

The collision of pre- and postsynaptic activity is known to provide a trigger for controlling the gain of synaptic transmission between neurons. Here, using in vivo intracellular recordings of rat striatal output neurons, we analyse the effect of a single action potential, generated by ongoing synaptic activity, on subsequent excitatory postsynaptic potentials (EPSPs) evoked by electrical stimulation of the cerebral cortex. This pairing induced a short-term increase in the probability that cortically evoked EPSPs caused striatal cells to fire. This enhanced EPSP-spike coupling was associated with a decrease in the voltage firing threshold with no apparent change in the synaptic strength itself. Antidromic action potentials in striatal cells were also able to induce the facilitation while subthreshold EPSPs were ineffective, indicating that the postsynaptic spike was necessary and sufficient for the induction of the plasticity. A prior spontaneous action potential also enhanced the probability with which directly applied current pulses elicited firing, suggesting that the facilitation originated from changes in the intrinsic electrical properties of the postsynaptic cell. Using whole-cell recordings in cortico-striatal slices, we found that the increase in membrane excitability as well as in EPSP-spike coupling was abolished by low concentration of 4-aminopyridine. This suggests that the intrinsic plasticity results from a time-dependent modulation of a striatal voltage-dependent potassium current available close to the firing threshold. Action potentials thus provide a postsynaptic signal, not only for associative synaptic plasticity but also for activity-dependent intrinsic plasticity, which directly controls the efficacy of coupling between pre- and postsynaptic neurons.