Selective cognitive dysfunction in mice lacking histamine H1 and H2 receptors

Previous pharmacological experiments provide conflicting findings that describe both facilitatory and inhibitory effects of neuronal histamine on learning and memory. Here, we examined learning and memory and synaptic plasticity in mice with a null mutation of gene coding histamine H1 or H2 receptor in order to clarify the role of these receptors in learning and memory processes. Learning and memory were evaluated by several behavioral tasks including object recognition, Barnes maze and fear conditioning. These behavioral tasks are highly dependent on the function of prefrontal cortex, hippocampus or amygdala. Object recognition and Barnes maze performance were significantly impaired in both H1 receptor gene knockout (H1KO) and H2 receptor gene knockout (H2KO) mice when compared to the respective wild-type (WT) mice. Conversely, both H1KO and H2KO mice showed better auditory and contextual freezing acquisition than their respective WT mice. Furthermore, we also examined long-term potentiation (LTP) in the CA1 area of hippocampus in H1KO and H2KO mice and their respective WT mice. LTP in the CA1 area of hippocampus was significantly reduced in both H1KO and H2KO mice when compared with their respective WT mice. In conclusion, our results demonstrate that both H1 and H2 receptors are involved in learning and memory processes for which the frontal cortex, amygdala and hippocampus interact.     

Taurine-transporter gene knockout-induced changes in GABAA, kainate and AMPA but not NMDA receptor binding in mouse brain

The aim of this study was to determine whether the knockout of the taurine-transporter gene in the mouse affects the densities of GABA_A, kainate, AMPA and NMDA receptors in the brain. The caudate-putamen, the hippocampus and its subregions, and the cerebellum of six homozygous taurine-transporter gene knockout mice and six wild-type (WT) animals were examined by means of quantitative receptor autoradiography. Saturation studies were carried out for all four receptor types in order to find possible intergroup differences in B _max and K _D values. Taurine-transporter gene knockout animals showed significantly higher GABA_A receptor densities in the molecular layer of the hippocampal dentate gyrus and in the cerebellum than did WT animals. The densities of kainate receptors were significantly higher in the caudate-putamen, the CA1 and hilus regions of the hippocampus and in the cerebellum of knockout animals. The caudate-putamen and cerebellum of these mice also contained significantly higher AMPA receptor densities. However, there were no significant differences between knockout and WT animals concerning the densities of NMDA receptors. Reduced brain taurine levels are associated with increased GABA_A, kainate and AMPA receptor densities in some of the regions we examined.     

Taurine-transporter gene knockout-induced changes in GABA(A), kainate and AMPA but not NMDA receptor binding in mouse brain

The aim of this study was to determine whether the knockout of the taurine-transporter gene in the mouse affects the densities of GABA_A, kainate, AMPA and NMDA receptors in the brain. The caudate-putamen, the hippocampus and its subregions, and the cerebellum of six homozygous taurine-transporter gene knockout mice and six wild-type (WT) animals were examined by means of quantitative receptor autoradiography. Saturation studies were carried out for all four receptor types in order to find possible intergroup differences in B _max and K _D values. Taurine-transporter gene knockout animals showed significantly higher GABA_A receptor densities in the molecular layer of the hippocampal dentate gyrus and in the cerebellum than did WT animals. The densities of kainate receptors were significantly higher in the caudate-putamen, the CA1 and hilus regions of the hippocampus and in the cerebellum of knockout animals. The caudate-putamen and cerebellum of these mice also contained significantly higher AMPA receptor densities. However, there were no significant differences between knockout and WT animals concerning the densities of NMDA receptors. Reduced brain taurine levels are associated with increased GABA_A, kainate and AMPA receptor densities in some of the regions we examined.     

Dynamic SAP102 expression in the hippocampal subregions of rats and APP/PS1 mice of various ages

The hippocampus is a structurally and functionally complex brain area that plays important and diverse roles in higher brain functions, such as learning and memory, and mounting evidence indicates that different hippocampal subregions play distinctive roles. The hippocampus is also one of the first regions in the brain to suffer damage in Alzheimer's disease (AD). Synaptic dysfunction in the hippocampus, rather than neuronal loss per se, is paralleled by behavioural and functional deficits in AD. The membrane‐associated guanylate kinase (MAGUK) family of proteins, including SAP102, PSD‐95, PSD‐93 and SAP97, have long been recognized as essential components of the postsynaptic density (PSD) at excitatory synapses. Hippocampal spines are the predominant synaptic transmission sites of excitatory glutamatergic synapses. During postnatal brain development, individual MAGUK members show distinct expression patterns. Although SAP102 has been confirmed as the dominant scaffold protein in neonatal synapses, its expression profiles in adult and ageing rodent hippocampi are discrepant. Furthermore, in AD brains, significantly reduced SAP102 protein levels have been found, suggesting that SAP102 may be related to AD progression; however, the precise mechanism underlying this result remains unclear. Herein, we observed distinct SAP102 expression profiles in the hippocampal CA1, CA3 and DG subregions of rats and APPswe/PS1dE9 (APP/PS1) mice at various ages using immunofluorescence. In Wistar rats, SAP102 was not only highly expressed in the hippocampal subregions of neonatal rats but also maintained relatively high expression levels in adult hippocampi and displayed no obvious decreases in the CA1 and DG subregions of aged rats. Surprisingly, we observed abnormally high SAP102 expression levels in the CA1 stratum moleculare and CA3 stratum polymorphum subregions of 2‐month‐old APP/PS1 mice, but low SAP102 levels in the DG and CA3 subregions of 7‐month‐old APP/PS1 mice, reflecting the subregion‐specific reactivity and vulnerability of AD mouse models in different disease stages. Our findings provide fundamental data to support the functional differences of SAP102 in different hippocampal subregions during postnatal periods and may serve as the basis for additional functional studies on SAP102 in normal physiological conditions and different stages of AD.     

Differential effects of L-trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with L-tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after L-tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, L-tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.     

Aging and sex differences in striatal dopaminergic function

In this report the potassium- (30 mM) and amphetamine- (10 microM) stimulated responses of dopamine (DA) and 3,4-dihydroxy phenylacetic acid (DOPAC) from superfused striatal tissue of female and male mice as sampled at 2, 6, 18 and 24 months of age were compared. When assessed relative to responses obtained from 2-month-old female mice, potassium-stimulated DA output of female mice was significantly decreased at 18 months of age and significantly increased at 24 months of age. In male mice, the only statistically significant change was an increase in potassium-stimulated DA in the 24 versus 2-month-old mice. In response to amphetamine-stimulation, DA responses from striatal tissue of 18-month-old females were significantly decreased and that of 24-month-old mice significantly increased relative to that of the 2-month-old females. In the case of male mice, amphetamine-stimulated DA responses of 6- and 18-month-old mice were significantly decreased compared with responses observed in the 2-month-old males.In addition, amphetamine-stimulated DA responses of the 24-month-old females were significantly greater than the 24-month-old males. In general, the response profiles for DOPAC to potassium and amphetamine stimulation were similar to that of DA for male, but not female, mice. These results demonstrate that sex differences in striatal dopaminergic function are differentially affected by age. Overall, striatal DA responsiveness of female mice shows more extreme age-related changes, particularly between the 2- and 6-month versus the 18- and 24-month-old mice and a discord between DA and DOPAC responses. Such extreme changes may be related to the presence (at 2 and 6 months) versus absence (at 18 and 24 months) of estrous cycles/gonadal steroid hormonal functions in female mice.     

Curcumin Ameliorates Memory Deficits by Enhancing Lactate Content and MCT2 Expression in APP/PS1 Transgenic Mouse Model of Alzheimer's Disease

Curcumin is a natural product with several anti-Alzheimer's disease (AD) neuroprotective properties. This study aimed to investigate the effects of curcumin on memory deficits, lactate content, and monocarboxylate transporter 2 (MCT2) in APP/PS1 mouse model of AD. APP/PS1 transgenic mice and wild-type (WT) C57BL/6J mice were used in the present study. Spatial learning and memory of the mice was detected using Morris water-maze test. Cerebral cortex and hippocampus lactate contents were detected using lactate assay. MCT2 expression in the cerebral cortex and hippocampus was examined by immunohistochemistry and Western blotting. Results showed that spatial learning and memory deficits were improved in curcumin-treated APP/PS1 mouse group compared with those in APP/PS1 mice group. Brain lactate content and MCT2 protein level were increased in curcumin-treated APP/PS1 mice than in APP/PS1 mice. In summary, our findings indicate that curcumin could ameliorate memory impairments in APP/PS1 mouse model of AD. This phenomenon may be at least partially due to its improving effect on the lactate content and MCT2 protein expression in the brain. Anat Rec, 302:332–338, 2019. © 2018 Wiley Periodicals, Inc.     

Induction of hypothermic conditions associated with increased micronuclei formation in sigma-1 receptor knockout mice after administration of the antipsychotic compound E-5842

The antipsychotic sigma-1 (sigma(1)) receptor ligand E-5842 has been shown to increase micronucleated polychromatic erythrocyte (MNPCE) frequency in mouse bone marrow secondary to compound-induced hypothermia. Interaction with sigma(1) receptor has been considered a plausible contributing factor for E-5842-induced hypothermia, raising concern for a possible class effect of sigma receptor ligands in the mouse micronucleus (MN) test. We assessed the potential of E-5842 (200 mg/kg, oral) to produce hypothermic conditions associated with increased micronuclei formation in sigma(1) receptor knockout (sigma(1)R-KO) and wild type (WT) mice. After administration, animal's rectal temperature was recorded and peripheral blood and bone marrow samples were obtained (48 hr) and assessed for induction of micronucleated reticulocytes (MNRET) and MNPCE, respectively. E-5842 administration produced marked hypothermia both in sigma(1)R-KO and WT mice. Maximum decreases from preadministration temperature were 12.2 and 13.5 degrees C in sigma(1)R-KO and WT mice, respectively. Temperature returned to normal approximately 32 hr after administration. Bone marrow examination revealed a statistical significant increase (P < 0.05) in MNPCE frequency both in sigma(1)R-KO and WT animals. Examination of peripheral blood samples showed a slight, although nonstatistical significant, increase in MNRET frequency in sigma(1)R-KO mice. No similar effect was observed among WT animals. The results obtained after E-5842 administration to sigma(1)R-KO mice indicate that induction of hypothermic conditions associated with increased MNPCE formation is not mediated by compound interaction with sigma(1) receptor, ruling out concern for a possible class effect of similar high affinity sigma(1) receptor ligands in the mouse MN test.     

Differential effects of -trytophan and buspirone on biogenic amine contents and metabolism in Lurcher mice cerebellum

The effects of serotoninergic stimulation on monoamines were studied in the heterozygous Lurcher (Lc/+) mutant mouse, a model of human cerebellar ataxia. Wild type (+/+) and Lc/+ mice were treated for 40 days with -tryptophan or buspirone, and serotonin (5-HT), dopamine (DA), noradrenaline (NA) and their main metabolites were measured in the cerebellum. In +/+ mice, only buspirone increased concentrations of 5-HT metabolites. In the hypoplastic Lc/+ cerebellum, indoleamines were higher, and increased further after both treatments. The 5-HT turnover index was increased in +/+ mice by buspirone, while in Lc/+ mutants it increased after -tryptophan but was decreased by buspirone, indicating that in the mutants nerve terminals synthesize and accumulate 5-HT, but may not utilize it efficiently. Catecholamine contents remained unchanged in +/+ mice, but in Lc/+ mutants with higher endogenous NA, -tryptophan further increased NA and 3,4-dihydroxy-phenylacetic acid (DOPAC), and buspirone augmented NA, DA and DOPAC levels.     

APP/PS1转基因小鼠海马内少突胶质细胞变化的体视学研究

目的:定量研究APP/PS1转基因小鼠海马内少突胶质细胞(OLG)的改变,探讨β-淀粉样蛋白(Aβ)对OLG的影响。方法:随机选取10月龄雄性APP/PS1转基因小鼠(AD组)和10月龄同窝生雄性野生型小鼠(WT组)各13只,运用Morris水迷宫检测各组小鼠的空间学习和记忆能力;运用体视学方法计数各组小鼠海马CA1、CA2-3和齿状回(DG)内Olig2+细胞和2',3'-环核苷酸3'-磷酸二酯酶(CNPase)阳性细胞总数;体外培养小鼠少突胶质前体细胞(MOPC),给予Aβ1-42,运用real time RT-PCR和Western Blot检测OLG相关蛋白的表达水平和含量。结果:AD小鼠逃避潜伏期显著性长于WT小鼠(P<0.05),穿台次数显著性少于WT小鼠(P<0.05);AD小鼠海马各区Olig2+细胞总数均较WT小鼠显著性增加(P<0.05),且与逃避潜伏期呈正相关,与穿台次数呈负相关,而各区CNPase+细胞总数均较WT小鼠显著性减少(P<0.05),且与逃避潜伏期呈负相关;Aβ1-42干预后MOPC的NG2及CNPase的mRNA水平显著性降低(P<0.05),Olig2含量也显著性降低(P<0.05)。结论:APP/PS1转基因小鼠海马内存在成熟OLG丢失、少突胶质细胞系异常增殖;Aβ可能引起OLG损伤和发育异常;保护海马成熟OLG以及调控OLG发育可能是防治AD的有效策略。     

Effects of optimized-SopungSunkiwon on memory impairment and enhancement

Optimized-SopungSunkiwon (OSS) is a multi-herbal formula that contains six medicinal herbs from SopungSunkiwon, a traditional medicine used for neurodegenerative disorders. In this study, we investigated the anti-amnesic effects of OSS in a dementia model. Acetylcholinesterase (AChE) inhibition assay was performed to investigate the cholinergic antagonistic effect of OSS. In addition, a step-through passive-avoidance test was performed with scopolamine-induced memory impairment in mice, and immunohistochemistry was analyzed to investigate synaptic formation with synaptic proteins. OSS inhibited AChE activity, resulting in significant improvement of memory functions. In the passive-avoidance test, the latency time of OSS-treated mice was significantly longer than that of either the control or scopolamine-treated group. In the immunohistochemical analysis, synaptic proteins such as synaptophysin and PSD-95 were significantly increased in OSS-treated mice. These results demonstrate that OSS may affect impairment and enhancement of memory and increase synaptophysin and PSD-95 facilitating acetylcholine release and synaptic growth.     

Chronic sleep deprivation altered the expression of circadian clock genes and aggravated Alzheimer's disease neuropathology

Circadian disruption is prevalent in Alzheimer''s disease (AD) and may contribute to cognitive impairment, psychological symptoms, and neurodegeneration. This study aimed to evaluate the effects of environmental and genetic factors on the molecular clock and to establish a link between circadian rhythm disturbance and AD. We investigated the pathological effects of chronic sleep deprivation (CSD) in the APP^swe/PS1^ΔE9 transgenic mice and their wild‐type (WT) littermates for 2 months and evaluated the expression levels of clock genes in the circadian rhythm‐related nuclei. Our results showed that CSD impaired learning and memory, and further exaggerated disease progression in the AD mice. Furthermore, CSD caused abnormal expression of Bmal1, Clock, and Cry1 in the circadian rhythm‐related nuclei of experimental mice, and these changes are more significant in AD mice. Abnormal expression of clock genes in AD mice suggested that the expression of clock genes is affected by APP/PS1 mutations. In addition, abnormal tau phosphorylation was found in the retrosplenial cortex, which was co‐located with the alteration of BMAL1 protein level. Moreover, the level of tyrosine hydroxylase in the locus coeruleus of AD and WT mice was significantly increased after CSD. There may be a potential link between the molecular clock, Aβ pathology, tauopathy, and the noradrenergic system. The results of this study provided new insights into the potential link between the disruption of circadian rhythm and the development of AD.     

Hippocampal Subregions are Differentially Affected in the Progression to Alzheimer's Disease

Atrophy within the hippocampus (HP) as measured by magnetic resonance imaging (MRI) is a promising biomarker for the progression to Alzheimer's disease (AD). Subregions of the HP along the longitudinal axis have been found to demonstrate unique function, as well as undergo differential changes in the progression to AD. Little is known of relationships between such HP subregions and other potential biomarkers, such as neuropsychological (NP), genetic, and cerebral spinal fluid (CSF) beta amyloid and tau measures. The purpose of this study was to subdivide the hippocampus to determine how the head, body, and tail were affected in normal control, mild cognitively impaired, and AD subjects, and investigate relationships with HP subregions and other potential biomarkers. MRI scans of 120 participants of the Alzheimer's Disease Neuroimaging Initiative were processed using FreeSurfer, and the HP was subdivided using 3D Slicer. Each subregion was compared among groups, and correlations were used to determine relationships with NP, genetic, and CSF measures. Results suggest that HP subregions are undergoing differential atrophy in AD, and demonstrate unique relationships with NP and CSF data. Discriminant function analyses revealed that these regions, when combined with NP and CSF measures, were able to classify by diagnostic group, and classify MCI subjects who would and would not progress to AD within 12 months. Anat Rec, 2012. © 2011 Wiley Periodicals, Inc.     

Effect of sex and age on brain monoamines and spatial learning in rats

The concentrations of noradrenaline (NA), dopamine (DA), serotonin (5-HT), and their metabolites were measured in the prefrontal cortex, caudate-putamen, and hippocampus in young (3 months) and aged (27–31 months) Wistar rats of both sexes. Age-related changes were found in prefrontal NA and HVA/DA ratio, striatal DA and DOPAC/DA ratio, and striatal and hippocampal 5-HT and 5-HIAA/5-HT ratio. Age and sex dependent changes were found in striatal DA and DOPAC/DA ratio, and hippocampal MHPG-SO₄/NA ratio. The aged rats were tested in spatial discrimination and reversal tasks in a T maze. The effects of α₂-agonist medetomidine (3 μg/kg) on the task performance were assessed in relation to individual variation in monoamine metabolism. Medetomidine impaired spatial discrimination learning of the aged rats by interacting with the hippocampal 5-HT turnover. Medetomidine improved reversal learning through an interaction with the striatal DA turnover and reduced the number of perseverative errors after reversal, mainly due to its interaction with the prefrontal NA turnover. It is concluded that the memory enhancing effect of drugs acting through the brain monoamine systems is highly dependent on the stage of degeneration of these systems that show considerable individual variation in aged animals.     

Aging and haloperidol-induced dopamine turnover in the nigro-striatal pathway of C57BL/6J mice

The responsiveness of male C57BL/6J mice to acute haloperidol (2.5 mg/kg, IP) was studied throughout the average adult lifespan (4, 8, 12, 21, 28 months) by effects on dopamine (DA) turnover, as estimated by DA loss after α-methyl-p-tyrosine (AMPT). Previously, striatal receptors for spiroperidol (a related butyrophenone) decreased progressively after 3 months to a loss of 40% by 28 months [29]. Haloperidol treatment (2 hours) accelerated striatal DA turnover similarly in all age groups, by about 100%. The haloperidol-induced accumulation of 3,4-dihydroxyphenylacetic acid (DOPAC) was not significantly impaired in AMPT treated mice with age. These results suggest that the age-related loss of butyrophenone binding sites may not limit acute compensatory responses to blockade of the remaining sites by a large dose of haloperidol. Regional differences in DA metabolism were detected between the substantia nigra (cell bodies and dendrites) and striatum (axonal terminals). Dopamine turnover and DOPAC levels were less in striatum than in substantia nigra; each region had a characteristic DOPAC/DA ratio (nigra, 38%; striatum, 7%); and, DOPAC levels did not precisely covary with DA turnover between regions. The constancy of DOPAC/DA ratios in conrols and after AMPT treatment, in all ages suggests that a constant fraction of DA continued to be released and catabolized to DOPAC despite major decrease of DA after blockade of synthesis of DA.     

神经干细胞移植对192-IgG-saporin老年性痴呆模型鼠的学习记忆及海马胆碱能纤维的影响

目的探讨神经干细胞(NSCs)移植对192-IgG-saporin致老年性痴呆模型鼠学习记忆和海马胆碱能纤维再生的影响。方法采用192-IgG-saporin(2.5μg/5μL)侧脑室注射SD大鼠建立痴呆模型后,行基底前脑神经干细胞移植,4周后行Y迷宫检测,并观察大鼠海马胆碱能纤维数的变化。结果Y迷宫检测显示大鼠的学习、记忆能力,模型组(107.38±9.34、3.75±0.71)与正常组比较明显下降(P<0.01),而移植组(75.26±5.33、5.45±0.51)有所改善(P<0.05);免疫组化显示模型组大鼠海马CA1区辐射层和齿状回分子层胆碱能阳性纤维,模型组与正常组比较,CA1辐射层和齿状回分子层纤维密度分别减少到11.07%和12.96%(P<0.01),与正常组比较均而干细胞移植组则分别恢复到正常组的81.39%和75.30%(P>0.05)。结论神经干细胞能促进192-IgG-saporinAD动物模型鼠学习记忆能力的恢复及海马胆碱能纤维的再生。     

Motor deficits in homozygous and heterozygous p/q-type calcium channel mutants

P/Q-type voltage-dependent Ca(2+) channels (VDCCs) are highly expressed in the cerebellum, and mutations of these channels are associated with disrupted motor function. Several allelic variants of the alpha1A pore-forming subunit of P/Q-type VDCCs have been described, and mice homozygous for these mutations exhibit gait ataxia, as do alpha1A knockout mice. Here we report that heterozygous alpha1A mutants also have a motor phenotype. Mice heterozygous for the leaner and alpha1A knockout mutations exhibit impaired motor learning in the vestibulo-ocular reflex (VOR), suggesting that subtle disruption of P/Q Ca(2+) currents is sufficient to disrupt motor function. Basal VOR and optokinetic reflex performance were normal in the heterozygotes but severely impaired in the leaner and alpha1A knockout homozygotes.     

Interferon-γ deficiency modifies the motor and co-morbid behavioral pathology and neurochemical changes provoked by the pesticide paraquat

In addition to nigrostriatal pathology and corresponding motor disturbances, Parkinson's disease (PD) is often characterized by co-morbid neuropsychiatric symptoms, most notably anxiety and depression. Separate lines of evidence indicate that inflammatory processes associated with microglial activation and cytokine release may be fundamental to the progression of both PD and its co-morbid psychiatric pathology. Accordingly, we assessed the contribution of the pro-inflammatory cytokine, interferon-gamma (IFN-γ), to a range of PD-like pathology provoked by the ecologically relevant herbicide and dopamine (DA) toxin, paraquat. To this end, paraquat provoked overt motor impairment (reduced home-cage activity and impaired vertical climbing) and signs of anxiety-like behavior (reduced open field exploration) in wild-type but not IFN-γ-deficient mice. Correspondingly, paraquat promoted somewhat divergent variations in neurochemical activity among wild-type and IFN-γ null mice at brain sites important for both motor (striatum) and co-morbid affective pathologies (dorsal hippocampus, medial prefrontal cortex, and locus coeruleus). Specifically, the herbicide provoked a dosing regimen-dependent reduction in striatal DA levels that was prevented by IFN-γ deficiency. In addition, the herbicide influenced serotonergic and noradrenergic activity within the dorsal hippocampus and medial prefrontal cortex; and elevated noradrenergic activity within the locus coeruleus. Although genetic ablation of IFN-γ had relatively few effects on monoamine variations within the locus coeruleus and prefrontal cortex, loss of the pro-inflammatory cytokine did normalize the paraquat-induced noradrenergic alterations within the hippocampus. These findings further elucidate the functional implications of paraquat intoxication and suggest an important role for IFN-γ in the striatal and motor pathology, as well as the co-morbid behavioral and hippocampal changes induced by paraquat.