The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain.

Neuropathic pain is a debilitating pathological condition of high clinical relevance. Changes in neuronal excitability in the anterior cingulate cortex (ACC) play a central role in the negative emotional and affective aspects of chronic pain. We evaluated the effects of LP-211, a new serotonin-receptor-type-7 (5-HT7R) agonist that crosses the blood-brain barrier, on ACC neurons in a mouse model of neuropathic pain. LP-211 reduced synaptic integration in layer 5 pyramidal neurons, which was enhanced in neuropathic pain due to a dysfunction of dendritic hyperpolarization-activated-and-cyclic-nucleotide-regulated (HCN) channels. Acute injection of LP-211 had an analgesic effect, increasing the mechanical withdrawal threshold in neuropathic animals, which was partially mediated by an action in the ACC. Additionally, the acute application of LP-211 blocked the switch in the place escape/avoidance behavior induced by noxious stimuli. Thus systemic treatment with a 5-HT7R agonist leads to modulation of the ACC, which dampens sensory and affective aspects of chronic pain.

Non-Hebbian long-term potentiation of inhibitory synapses in the thalamus.

The thalamus integrates and transmits sensory information to the neocortex. The activity of thalamocortical relay (TC) cells is modulated by specific inhibitory circuits. Although this inhibition plays a crucial role in regulating thalamic activity, little is known about long-term changes in synaptic strength at these inhibitory synapses. Therefore, we studied long-term plasticity of inhibitory inputs to TC cells in the posterior medial nucleus of the thalamus by combining patch-clamp recordings with two-photon fluorescence microscopy in rat brain slices. We found that specific activity patterns in the postsynaptic TC cell induced inhibitory long-term potentiation (iLTP). This iLTP was non-Hebbian because it did not depend on the timing between presynaptic and postsynaptic activity, but it could be induced by postsynaptic burst activity alone. iLTP required postsynaptic dendritic Ca(2+) influx evoked by low-threshold Ca(2+) spikes. In contrast, tonic postsynaptic spiking from a depolarized membrane potential (-50 mV), which suppressed these low-threshold Ca(2+) spikes, induced no plasticity. The postsynaptic dendritic Ca(2+) increase triggered the synthesis of nitric oxide that retrogradely activated presynaptic guanylyl cyclase, resulting in the presynaptic expression of iLTP. The dependence of iLTP on the membrane potential and therefore on the postsynaptic discharge mode suggests that this form of iLTP might occur during sleep, when TC cells discharge in bursts. Therefore, iLTP might be involved in sleep state-dependent modulation of thalamic information processing and thalamic oscillations.

Astrocyte signaling controls spike timing-dependent depression at neocortical synapses.

Endocannabinoid mediated spike timing-dependent depression (t-LTD) is crucially involved in the development of the sensory neocortex. t-LTD at excitatory synapses in the developing rat barrel cortex requires cannabinoid CB(1) receptor (CB(1)R) activation, as well as activation of NMDA receptors located on the presynaptic terminal, but the exact signaling cascade leading to t-LTD remains unclear. We found that astrocytes are critically involved in t-LTD. Astrocytes gradually increased their Ca(2+) signaling specifically during the induction of t-LTD in a CB(1)R-dependent manner. In this way, astrocytes might act as a memory buffer for previous coincident neuronal activity. Following activation, astrocytes released glutamate, which activated presynaptic NMDA receptors to induce t-LTD. Astrocyte stimulation coincident with afferent activity resulted in long-term depression, indicating that astrocyte activation is sufficient for the induction of synaptic depression. Taken together, our findings describe the retrograde signaling cascade underlying neocortical t-LTD. The critical involvement of astrocytes in this process highlights their importance for experience-dependent sensory remodeling.

Single spine Ca2+ signals evoked by coincident EPSPs and backpropagating action potentials in spiny stellate cells of layer 4 in the juvenile rat somatosensory barrel cortex.

The precise timing of presynaptic and postsynaptic activity results in synaptic modifications, which depend on calcium influx. [Ca2+] transients in the spines of spiny neurons in layer 4 (L4) of the somatosensory barrel cortex of young rats were investigated in thalamocortical brain slices by two-photon excitation microscopy to determine the spike timing dependence of the Ca2+ signal during near-coincident presynaptic and postsynaptic activity. [Ca2+] transients evoked by backpropagating action potentials (bAPs) were mediated by voltage-dependent Ca2+ channels and were of comparable size in a spine and adjacent dendritic shaft. They decreased with the distance of the spine from the soma. EPSP-evoked [Ca2+] transients were restricted to spine heads and were mediated almost entirely by Ca2+ influx through NMDA receptors (NMDARs). Their amplitude was independent of the position of the spine along the dendritic arbor. bAPs interacted with EPSPs to generate sublinear or supralinear Ca2+ signals in a spine when EPSP and bAP occurred within a time window of 50 msec. Synaptic stimulation, coincident with a bAP, evoked a large postsynaptic Ca2+ influx that was restricted to a single spine, even after EPSPs were blocked by the AMPA receptor antagonist NBQX that rendered synapses effectively "electrically silent." We conclude that the spines of L4 cells can act as sharply tuned detectors for patterns of APs occurring in the boutons of the afferents to L4 cells and the spines of L4 cell dendrites. The readout for near-coincident presynaptic and postsynaptic APs is a large transient Ca2+ influx into synaptically active spines mediated by the brief unblocking of NMDARs during the dendritic bAP.