Synergistic activation of phosphoinositide hydrolysis induced in brain slices by norepinephrine and the excitatory amino acid agonist, Trans-ACPD

Norepinephrine and trans-1-aminocyclopentyl-1,3-dicarboxylic acid (ACPD) each individually stimulated hydrolysis of phosphoinositides and when tested in combination caused a stimulation that was 50–90% greater than additive in hippocampal and cortical slices of the rat but not in striatal slices. This synergistic augmentation of hydrolysis of phosphoinositide was evident with all stimulatory concentrations of norepinephrine and of ACPD up to 1 mM, at which point ACPD was inhibitory. A time-course study revealed no lag in the synergistic interaction and no down-regulation through 60 min of incubation of the augmented response to the combined agonists. The synergistic reaction was mediated by α 1-adrenergic receptors and by metabotropic excitatory amino acid receptors. Increased intracellular calcium, but not activation of protein kinase C, may play a role in mediating the synergistic interaction. Thus, a unique synergistic stimulatory interaction was found between two receptors coupled with phosphoinositide metabolism, a finding which also supports the suggestion that these two systems are co-localized in some cells

Abstract # 2067 Pathogenic hippocampal Th17 cells linked to depressive-like behavior in mice

Depression is prevalent and debilitating and has been linked to inflammation. Inflammation is associated with increases in CD4 cells that produce IL-17A (Th17 cells) that promote depression in mice. We examined the mechanisms by which Th17 cells promote depressive-like behaviors. Th17 cells, but not Th1 cells, promoted depressive-like behaviors, and Th17 cells accumulated in the prefrontal cortex and hippocampus, but not in cerebellum, of mice exhibiting stress-induced learned helplessness depressive-like behavior. Adoptive transfer of Th17 cells into Rag2−/− mice, which are devoid of endogenous T cells, was sufficient to promote susceptibility to learned helplessness, demonstrating that increased peripheral Th17 cells can affect behavior. Moreover, adoptively transferred Th17 cells accumulated in the hippocampus of learned helpless mice, and induced endogenous Th17 cell differentiation. Characterization of hippocampal Th17 cells in learned helpless mice revealed that the Th17 cells express CCR6 and IL-23R, which have previously been shown to be markers of pathogenic Th17 cells, and CXCR5, a marker of follicular T cells. CCR6, but not CXCR5, was required to promote Th17 cell-dependent depressive-like behavior. PD-1 expression on Th17 cells was increased in the mice that received CCR6 deficient Th17 cells, providing a possible link between T follicular cells expressing PD-1 and pathogenic CCR6 expressing Th17 cells in the brain. In conclusion, Th17 cells and associated pathways may be novel molecular targets for depression

Acetylcholine content in rat brain is elevated by status epilepticus induced by lithium and pilocarpine

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Dose- and time-dependent hippocampal cholinergic lesions induced by ethylcholine mustard aziridinium ion: effects of nerve growth factor, GM1 ganglioside and vitamin E

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Lack of excitatory amino acids-induced effects on calcium fluxes measured with 45Ca2+ in rat cerebral cortex synaptosomes

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Disruption of circadian rhythmicity and suprachiasmatic action potential frequency in a mouse model with constitutive activation of glycogen synthase kinase 3

Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in psychiatric diseases, neurodevelopment, and circadian regulation. Both GSK3 isoforms, α and β, exhibit a 24-hour variation of inhibitory phosphorylation within the suprachiasmatic nucleus (SCN), the primary circadian pacemaker. We examined the hypothesis that rhythmic GSK3 activity is critical for robust circadian rhythmicity using GSK3α(21A/21A)/β(9A/9A) knock-in mice with serine-alanine substitutions at the inhibitory phosphorylation sites, making both forms constitutively active. We monitored wheel-running locomotor activity of GSK3 knock-in mice and used loose-patch electrophysiology to examine the effect of chronic GSK3 activity on circadian behavior and SCN neuronal activity. Double transgenic GSK3α/β knock-in mice exhibit disrupted behavioral rhythmicity, including significantly decreased rhythmic amplitude, lengthened active period, and increased activity bouts per day. This behavioral disruption was dependent on chronic activation of both GSK3 isoforms and was not seen in single transgenic GSK3α or GSK3β knock-in mice. Underlying the behavioral changes, SCN neurons from double transgenic GSK3α/β knock-in mice exhibited significantly higher spike rates during the subjective night compared to those from WT controls, with no differences detected during the subjective day. These results suggest that constitutive activation of GSK3 results in loss of the typical day/night variation of SCN neuronal activity. Together, these results implicate GSK3 activity as a critical regulator of circadian behavior and neurophysiological rhythms. Because GSK3 has been implicated in numerous pathologies, understanding how GSK3 modulates circadian rhythms and neurophysiological activity may lead to novel therapeutics for pathological disorders and circadian rhythm dysfunction