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Genetic alterations or pharmacological treatments affecting endocannabinoid signaling have profound effects on synaptic and neuronal properties and, under certain conditions, may improve higher brain functions. Down syndrome (DS), a developmental disorder caused by triplication of chromosome 21, is characterized by deficient cognition and inevitable development of the Alzheimer disease (AD) type pathology during aging. Here we used JZL184, a selective inhibitor of monoacylglycerol lipase (MAGL), to examine the effects of chronic MAGL inhibition on the behavioral, biochemical, and synaptic properties of aged Ts65Dn mice, a genetic model of DS. In both Ts65Dn mice and their normosomic (2N) controls, JZL184-treatment increased brain levels of 2-arachidonoylglycerol (2-AG) and decreased levels of its metabolites such as arachidonic acid, prostaglandins PGD2, PGE2, PGFα, and PGJ2. Enhanced spontaneous locomotor activity of Ts65Dn mice was reduced by the JZL184-treatement to the levels observed in 2N animals. Deficient long-term memory was also improved, while short-term and working types of memory were unaffected. Furthermore, reduced hippocampal long-term potentiation (LTP) was increased in the JZL184-treated Ts65Dn mice to the levels observed in 2N mice. Interestingly, changes in synaptic plasticity and behavior were not observed in the JZL184-treated 2N mice suggesting that the treatment specifically attenuated the defects in the trisomic animals. The JZL184-treatment also reduced the levels of Aβ40 and Aβ42, but had no effect on the levels of full length APP and BACE1 in both Ts65Dn and 2N mice. These data show that chronic MAGL inhibition improves the behavior and brain functions in a DS model suggesting that pharmacological targeting of MAGL may be considered as a perspective new approach for improving cognition in DS.

BackgroundMaintaining pH levels within the physiological norm is an important component of brain homeostasis. However, in some pathological or physiological conditions, the capacity of the pH regulatory system could be overpowered by various factors resulting in a transient or permanent alteration in pH levels. Such changes are often observed in pathological conditions associated with neuroinflammation. We hypothesized that neuroinflammation itself is a factor affecting pH levels in neural tissue. To assess this hypothesis, we examined the effects of acute LPS-induced neuroinflammation on intra- and extracellular pH (pHi and pHo) levels in the CA1 region of mouse hippocampus.MethodsAcute neuroinflammation was induced using two approaches: (1) in vivo by i.p. injections of LPS (5 mg/kg) and (2) in vitro by incubating hippocampal slices of naïve animals in the LPS-containing media (1 μg/mL, 1 h at 35 °C). Standard techniques were used to prepare hippocampal slices. pHi was measured using ratiometric pH-sensitive fluorescent dye BCECF-AM. pHo was assessed using calibrated pH-sensitive micropipettes. The presence of neuroinflammation was verified with immunohistochemistry (IL-1β and Iba1) and ELISA (IL-1β and TNF-α).ResultsA significant reduction of pHi was observed in the slices of the LPS-injected 3-month-old (LPS 7.13 ± 0.03; Sal 7.22 ± 0.03; p = 0.043, r = 0.43) and 19-month-old (LPS 6.78 ± 0.08; Sal 7.13 ± 0.03; p = 0.0001, r = 0.32) mice. In contrast, the levels of pHo within the slice, measured in 19-month-old animals, were not affected (LPS 7.27 ± 0.02; Sal 7.26 ± 0.02; p = 0.6, r = 0.13). A reduction of pHi was also observed in the LPS-treated slices during the interval 3.5–7 h after the LPS exposure (LPS 6.92 ± 0.07; Veh 7.28 ± 0.05; p = 0.0001, r = 0.46).ConclusionsAcute LPS-induced neuroinflammation results in a significant intracellular acidification of the CA1 neurons in mouse hippocampus, while the pHo remains largely unchanged. Such changes may represent a specific protective reaction of neural tissue in unfavorable external conditions or be a part of the pathological process.Electronic supplementary materialThe online version of this article (doi:10.1186/s12974-016-0747-8) contains supplementary material, which is available to authorized users.

Introduction: Neuropathic pain manifests in a diverse combination of sensory symptoms and disorders of higher nervous activity, such as memory deficiency, anxiety, depression, anhedonia, etc. This suggests the participation of brain structures, including the hippocampus, in the pathogenesis of neuropathic pain. The elucidation of central sensitization mechanisms underlying neuropathic pain cognitive and affective symptoms may be useful in the development of new and effective treatments for these common disorders. The study aims to elucidate the effect of chronic neuropathic pain on cognitive function and underlying neuronal plasticity in the hippocampus. Methods: Chronic constriction injury of mouse right hind limb sciatic nerve was used as a model of neuropathic pain. The presence of neuropathic pain was confirmed by the thermal and mechanical allodynia. The morphology of the CA1 pyramidal neurons and the dentate gyrus (DG) granule neurons were studied using Golgi-Cox staining. The hippocampal proteins concentration was determined by immunohistochemistry and ELISA. Results: Behavioral testing revealed reduced locomotor activity as well as impaired working and long-term memory in mice with a ligated nerve. We revealed changes in the dendritic tree morphology in CA1 and the dentate gyrus hippocampal subregions. We found the atrophy of the CA1 pyramidal neurons and an increase in the dendritic tree complexity in DG. Moreover, changes in the density of dendritic spines were observed in these regions. In addition, we revealed increased expression of the Arc protein in DG granule neurons and decreased surface expression of AMPA receptors within the hippocampus. Decreased AMPA receptors expression underlies observed altered dendrite arborization and dendritic spines morphology. Discussion: We found that pain information entering the hippocampus causes neuronal plasticity changes. The changes in neurite arborization, dendritic length and dendritic spines morphology as well as protein expression are observed within the hippocampal regions involved in the processing of pain information. Moreover, changes in the dendrite morphology in hippocampal subregions are different due to the anatomical and functional heterogeneity of the hippocampus. Apparently, the detected morphological and biochemical changes can underlie the observed hippocampus-dependent behavioral and cognitive impairment in animals with neuropathic pain.