Large-scale animal model study uncovers altered brain pH and lactate levels as a transdiagnostic endophenotype of neuropsychiatric disorders involving cognitive impairment.

Increased levels of lactate, an end-product of glycolysis, have been proposed as a potential surrogate marker for metabolic changes during neuronal excitation. These changes in lactate levels can result in decreased brain pH, which has been implicated in patients with various neuropsychiatric disorders. We previously demonstrated that such alterations are commonly observed in five mouse models of schizophrenia, bipolar disorder, and autism, suggesting a shared endophenotype among these disorders rather than mere artifacts due to medications or agonal state. However, there is still limited research on this phenomenon in animal models, leaving its generality across other disease animal models uncertain. Moreover, the association between changes in brain lactate levels and specific behavioral abnormalities remains unclear. To address these gaps, the International Brain pH Project Consortium investigated brain pH and lactate levels in 109 strains/conditions of 2294 animals with genetic and other experimental manipulations relevant to neuropsychiatric disorders. Systematic analysis revealed that decreased brain pH and increased lactate levels were common features observed in multiple models of depression, epilepsy, Alzheimer's disease, and some additional schizophrenia models. While certain autism models also exhibited decreased pH and increased lactate levels, others showed the opposite pattern, potentially reflecting subpopulations within the autism spectrum. Furthermore, utilizing large-scale behavioral test battery, a multivariate cross-validated prediction analysis demonstrated that poor working memory performance was predominantly associated with increased brain lactate levels. Importantly, this association was confirmed in an independent cohort of animal models. Collectively, these findings suggest that altered brain pH and lactate levels, which could be attributed to dysregulated excitation/inhibition balance, may serve as transdiagnostic endophenotypes of debilitating neuropsychiatric disorders characterized by cognitive impairment, irrespective of their beneficial or detrimental nature.

Comprehensive behavioral analysis of ENU-induced Disc1-Q31L and -L100P mutant mice.

BACKGROUND: Disrupted-in-Schizophrenia 1 (DISC1) is considered to be a candidate susceptibility gene for psychiatric disorders, including schizophrenia, bipolar disorder, and major depression. A recent study reported that N-ethyl-N-nitrosourea (ENU)-induced mutations in exon 2 of the mouse Disc1 gene, which resulted in the amino acid exchange of Q31L and L100P, caused an increase in depression-like behavior in 31 L mutant mice and schizophrenia-like behavior in 100P mutant mice; thus, these are potential animal models of psychiatric disorders. However, remaining heterozygous mutations that possibly occur in flanking genes other than Disc1 itself might induce behavioral abnormalities in the mutant mice. Here, to confirm the effects of Disc1-Q31L and Disc1-L100P mutations on behavioral phenotypes and to investigate the behaviors of the mutant mice in more detail, the mutant lines were backcrossed to C57BL/6JJcl through an additional two generations and the behaviors were analyzed using a comprehensive behavioral test battery. RESULTS: Contrary to expectations, 31 L mutant mice showed no significant behavioral differences when compared with wild-type control mice in any of the behavioral tests, including the Porsolt forced swim and tail suspension tests, commonly used tests for depression-like behavior. Also, 100P mutant mice exhibited no differences in almost all of the behavioral tests, including the prepulse inhibition test for measuring sensorimotor gating, which is known to be impaired in schizophrenia patients; however, 100P mutant mice showed higher locomotor activity compared with wild-type control mice in the light/dark transition test. CONCLUSIONS: Although these results are partially consistent with the previous study in that there was hyperactivity in 100P mutant mice, the vast majority of the results are inconsistent with those of the previous study; this discrepancy may be explained by differences in the genetic background of the mice, the laboratory environment, experimental protocols, and more. Further behavioral studies under various experimental conditions are necessary to determine whether these Disc1 mutant mouse lines are suitable animal models of schizophrenia and major depression.

Proatherogenic effect of interleukin-18 is exerted with high-fat diet, but not with normal diet in spontaneously hyperlipidemic mice.

AIM: It has been considered that interleukin (IL)-18, a T helper 1(Th1) type cytokine, has a promoting effect on atherosclerosis development. A previous mouse study demonstrated that short-term exogenous IL-18 promoted atherosclerosis through a Th1 type immune response; however, the serum IL-18 may have increased greatly beyond its physiological range, and the effect of increased serum IL-18 on atherosclerosis development has not been investigated under different conditions of dietary fat content. The purpose of this study was to reveal the effect of increased serum IL-18 within its physiological fluctuations on atherosclerosis development under different conditions of dietary fat content. METHODS: Spontaneously hyperlipidemic (SHL) mice were systemically supplied with IL-18 for 10 weeks by means of an in vivo gene transfer system with a high-fat diet containing 0.15% cholesterol or a normal diet. RESULTS: Serum IL-18 steadily elevated within its physiological fluctuations. An atherosclerotic lesion area in the aortic root significantly increased with a high-fat diet. Systemic cytokine balance shifted to a Th1-dominant state, and IL-12 mRNA in the arterial wall significantly increased with a high-fat diet; however, these findings were not observed with a normal diet. CONCLUSIONS: It was suggested that the proatherogenic effect of IL-18 is physiologically exerted exclusively with a high-fat diet through Th1 type immune responses, but not with a normal diet.

Stabilization of mast cells by heme oxygenase-1: an anti-inflammatory role.

This study examined the role of bilirubin in heme oxygenase (HO)-1-mediated amelioration of mast cell (MC)-elicited inflammatory responses. Pretreatment of rats with an intraperitoneal injection of hemin, an inducer of HO-1, evolved a marked induction of the enzyme in MCs. Intravital videomicroscopy revealed that hemin pretreatment attenuated compound 48/80-elicited degranulation of MCs and resultant leukocyte adhesion in venules. Superfusion with biliverdin or bilirubin, but not with carbon monoxide (CO), another product of the HO reaction, mimicked suppressive actions of the HO-1 induction on both the cell degranulation and leukocyte adhesion elicited by the stimulus, suggesting a requirement of the enzyme reaction to generate bilirubin in the inhibitory mechanisms. Such MC-desensitizing actions of bilirubin were observed in primary-cultured MCs and reproduced irrespective of the choice of stimuli, such as compound 48/80, calcium ionophore, and anti-IgE serum. Furthermore, MC-stabilizing effects of HO-1 were reproduced by the gene transfection of the enzyme into mastocytoma cell line RBL2H3. These results suggest that bilirubin generated through HO-1 serves as an anti-inflammatory substance that desensitizes MCs and ameliorates leukocyte recruitment.