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The background potassium channel TREK-1 has been shown to be a potent target for depression treatment. Indeed, deletion of this channel in mice resulted in a depression resistant phenotype. The association of TREK-1 with the sorting protein sortilin prompted us to investigate the behavior of mice deleted from the gene encoding sortilin (Sort1−/−). To characterize the consequences of sortilin deletion on TREK-1 activity, we combined behavioral, electrophysiological and biochemical approaches performed in vivo and in vitro. Analyses of Sort1−/− mice revealed that they display: (1) a corticosterone-independent anxiety-like behavior, (2) a resistance to depression as demonstrated by several behavioral tests, and (3) an increased activity of dorsal raphe nucleus neurons. All these properties were associated with TREK-1 action deficiency consequently to a decrease of its cell surface expression and to the modification of its electrophysiological activity. An increase of BDNF expression through activation of the furin-dependent constitutive pathway as well as an increase of the activated BDNF receptor TrkB were in agreement with the decrease of depressive-like behavior of Sort1−/− mice. Our results demonstrate that the TREK-1 expression and function are altered in the absence of sortilin confirming the importance of this channel in the regulation on the mood as a crucial target to treat depression.

Depression is a devastating mental disorder that affects 20% of the population worldwide. Despite their proven efficacy, antidepressants present a delayed onset of action and serious adverse effects. Seven years ago, we described spadin (PE 12-28) as a promising endogenous peptide with antidepressant activity. Spadin specifically blocks the TREK-1 channel. Previously, we showed in vivo that, spadin activity disappeared beyond 7 h after administration. In order to improve in vivo spadin stability and bioavailability, we screened spadin analogs and derivatives. From the study of spadin blood degradation products, we designed a 7 amino-acid peptide, PE 22-28. In vitro studies on hTREK-1/HEK cells by using patch-clamp technique, showed that PE 22-28 displayed a better specificity and affinity for TREK-1 channel compared to spadin, IC50 of 0.12 nM vs. 40–60 nM for spadin. In the same conditions, we also pointed out that different modifications of its N or C-terminal ends maintained or abolished TREK-1 channel activity without affecting PE 22-28 affinity. In vivo, the antidepressant properties of PE 22-28 and its derivatives were demonstrated in behavioral models of depression, such as the forced swimming test. Mice treated with spadin-analogs showed a significant reduction of the immobility time. Moreover, in the novelty suppressed feeding test after a 4-day sub-chronic treatment PE 22-28 reduced significantly the latency to eat the food pellet. PE 22-28 and its analogs were able to induce neurogenesis after only a 4-day treatment with a prominent effect of the G/A-PE 22-28. On mouse cortical neurons, PE 22-28 and its derivatives enhanced synaptogenesis measured by the increase of PSD-95 expression level. Finally, the action duration of PE 22-28 and its analogs was largely improved in comparison with that of spadin, up to 23 h instead of 7 h. Taken together, our results demonstrated that PE 22-28 and its derivatives represent other promising molecules that could be an alternative to spadin in the treatment of depression.

The neuropeptide neurotensin (NT) elicits numerous pharmacological effects through three different receptors (NTSR1, NTSR2 and NTSR3 also called sortilin). Pharmacological approaches and generation of NTSR1 and NTSR2-deficient mice allowed to determine the NT-induced antipsychotic like behaviour, the inhibitory of weak fear memory and the nociceptive signaling in a rat formalin tonic pain model to NTSR1. Conversely, the effects of NT on thermal and tonic nociceptions were mediated by NTSR2. However, the role of NTSR3/sortilin on the neurotensinergic system was not investigated. Here, by using C57Bl/6J mouse model in which the gene coding for NTSR3/sortilin has been inactivated, we observed a modification of the expression of both NTSR2 and NT itself. Quantitative PCR and protein expression using Western blot analyses and AlphaLisaTM technology resulted in the observation that brain NTSR2 as well as brain and blood NT were two fold increased in KO mice leading to a resistance of these mice to thermal and chemical pain. These data confirm that NTSR3/sortilin interacts with other NT receptors (ie ; NTSR2) and that its deletion modifies also the affinity of this receptor to NT.

Inhibition of the potassium channels TREK-1 by spadin (SPA) is currently thought to be a promising therapeutic target for the treatment of depression. Since these channels are expressed in pancreatic β-cells, we investigated their role in the control of insulin secretion and glucose homeostasis. In this study, we confirmed the expression of TREK-1 channels in the insulin secreting MIN6-B1 β-cell line and in mouse islets. We found that their blockade by SPA potentiated insulin secretion induced by potassium chloride dependent membrane depolarization. Inhibition of TREK-1 by SPA induced a decrease of the resting membrane potential (ΔVm~12 mV) and increased the cytosolic calcium concentration. In mice, administration of SPA enhanced the plasma insulin level stimulated by glucose, confirming its secretagogue effect observed in vitro. Taken together, this work identifies SPA as a novel potential pharmacological agent able to control insulin secretion and glucose homeostasis.

Alzheimer's disease (AD) is a progressive memory loss and cognitive dysfunction brain disorder brought on by the dysfunctional amyloid precursor protein (APP) processing and clearance of APP peptides. Increased APP levels lead to the production of AD-related peptides including the amyloid APP intracellular domain (AICD) and amyloid beta (Aβ), and consequently modify the intrinsic excitability of the hippocampal CA1 pyramidal neurons, synaptic protein activity, and impair synaptic plasticity at hippocampal CA1–CA3 synapses. The goal of the present study is to build computational models that incorporate the effect of AD-related peptides on CA1 pyramidal neuron and hippocampal synaptic plasticity under the AD conditions and investigate the potential pharmacological treatments that could normalize hippocampal synaptic plasticity and learning in AD. We employ a phenomenological N-methyl-D-aspartate (NMDA) receptor-based voltage-dependent synaptic plasticity model that includes the separate receptor contributions on long-term potentiation (LTP) and long-term depression (LTD) and embed it into the a detailed compartmental model of CA1 pyramidal neuron. Modeling results show that partial blockade of Glu2NB-NMDAR-gated channel restores intrinsic excitability of a CA1 pyramidal neuron and rescues LTP in AICD and Aβ conditions. The model provides insight into the complex interactions in AD pathophysiology and suggests the conditions under which the synchronous activation of a cluster of synaptic inputs targeting the dendritic tree of CA1 pyramidal neuron leads to restored synaptic plasticity.