Cannabinoid type 2 receptor inhibition enhances the antidepressant and proneurogenic effects of physical exercise after chronic stress.

Chronic stress is a major risk factor for neuropsychiatric conditions such as depression. Adult hippocampal neurogenesis (AHN) has emerged as a promising target to counteract stress-related disorders given the ability of newborn neurons to facilitate endogenous plasticity. Recent data sheds light on the interaction between cannabinoids and neurotrophic factors underlying the regulation of AHN, with important effects on cognitive plasticity and emotional flexibility. Since physical exercise (PE) is known to enhance neurotrophic factor levels, we hypothesised that PE could engage with cannabinoids to influence AHN and that this would result in beneficial effects under stressful conditions. We therefore investigated the actions of modulating cannabinoid type 2 receptors (CB2R), which are devoid of psychotropic effects, in combination with PE in chronically stressed animals. We found that CB2R inhibition, but not CB2R activation, in combination with PE significantly ameliorated stress-evoked emotional changes and cognitive deficits. Importantly, this combined strategy critically shaped stress-induced changes in AHN dynamics, leading to a significant increase in the rates of cell proliferation and differentiation of newborn neurons, overall reduction in neuroinflammation, and increased hippocampal levels of BDNF. Together, these results show that CB2Rs are crucial regulators of the beneficial effects of PE in countering the effects of chronic stress. Our work emphasises the importance of understanding the mechanisms behind the actions of cannabinoids and PE and provides a framework for future therapeutic strategies to treat stress-related disorders that capitalise on lifestyle interventions complemented with endocannabinoid pharmacomodulation.

Deep Brain Stimulation of the dorsal raphe abolishes serotonin 1A facilitation of AMPA receptor-mediated synaptic currents in the ventral hippocampus.

In a previous study we showed that Deep Brain Stimulation (DBS) of the rat dorsal subregion of the dorsal raphe (DRD), which sends serotonergic projections to forebrain areas, such as the ventral hippocampus, induces anxiolytic-like effects. The purpose of the present study was to investigate neurobiological alterations which might underline these behavioral effects. For that, we tested the influence of DBS upon the neuromodulatory action of serotonin on excitatory post-synaptic currents (EPSCs) in the ventral hippocampus. Male Wistar rats were submitted to high-frequency stimulation (100 µA, 100 Hz) of the DRD for 1 h during three consecutive days. On the third day, immediately after the DBS procedure, animals were euthanized. Slices of the ventral hippocampus were processed for whole cell patch clamp recordings of AMPA-receptor (AMPAR) mediated EPSCs in the CA1 area. As reported by others, we confirmed that in pre-weaning rats a high affinity 5-HT1A receptor agonist (8-OH-PIPAT, 0.5-5nM) inhibits EPSCs. However, in adult rats (non-operated or sham-operated), 8-OH-PIPAT (0.5-5 nM) increased EPSC amplitude, an effect blocked by the 5-HT1A antagonist WAY-100,635 (200 nM). Importantly, in adult rats exposed to DBS, the 5-HT1A agonist was devoid of effect. Taken together these results show that: 1) changes in 5-HT1A receptor-mediated hippocampal synaptic transmission occur with age; 2) these changes lead to a facilitatory effect of 5-HT1A receptors; 3) DBS blocks this serotonergic facilitatory action. These observations suggest that an alteration in serotonin modulation of limbic areas may underlie the psychotherapeutic effects of DBS.

Hippocampal synaptic dysfunction in the SOD1G93A mouse model of Amyotrophic Lateral Sclerosis: Reversal by adenosine A2AR blockade.

Amyotrophic Lateral Sclerosis (ALS) mostly affects motor neurons, but non-motor neural and cognitive alterations have been reported in ALS mouse models and patients. Here, we evaluated if time-dependent biphasic changes in synaptic transmission and plasticity occur in hippocampal synapses of ALS SOD1G93A mice. Recordings were performed in hippocampal slices of SOD1G93A and age-matched WT mice, in the pre-symptomatic and symptomatic stages. We found an enhancement of pre-synaptic function and increased adenosine A2A receptor levels in the hippocampus of pre-symptomatic mice. In contrast, in symptomatic mice, there was an impairment of long-term potentiation (LTP) and a decrease in NMDA receptor-mediated synaptic currents, with A2AR levels also being increased. Chronic treatment with the A2AR antagonist KW-6002, rescued LTP and A2AR values. Altogether, these findings suggest an increase in synaptic function during the pre-symptomatic stage, followed by a decrease in synaptic plasticity in the symptomatic stage, which involves over-activation of A2AR from early disease stages.