Sexually dimorphic expression of Usp9x is related to sex chromosome complement in adult mouse brain

We found the expression of Usp9x, an X-linked gene which encodes a ubiquitin protease implicated in synaptic development, to be significantly higher in the adult female mouse brains than in male brains. The sex difference in expression of Usp9x was localized to specific brain regions such as neocortex. Furthermore, in gonadally intact and gonadectomized mice, XX mice expressed Usp9x mRNA and protein more highly than XY mice irrespective of their gonadal type. No sex difference was found in the neonatal brain or peripheral tissues such as the adult kidney. This finding implies that the difference in sex chromosome complement between XY males and XX females could potentially contribute to sexual differentiation of brain structure and function. The relation of genomic dose and Usp9x expression could help explain the neural and behavioural phenotype of women with XO Turner syndrome.     

Region‐specific impairments in striatal synaptic transmission and impaired instrumental learning in a mouse model of Angelman syndrome

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by mental retardation and impaired speech. Because patients with this disorder often exhibit motor tremor and stereotypical behaviors, which are associated with basal ganglia pathology, we hypothesized that AS is accompanied by abnormal functioning of the striatum, the input nucleus of the basal ganglia. Using mutant mice with maternal deficiency of AS E6‐AP ubiquitin protein ligase Ube3a (Ube3a^m?/p+), we assessed the effects of Ube3a deficiency on instrumental conditioning, a striatum‐dependent task. We used whole‐cell patch‐clamp recording to measure glutamatergic transmission in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS). Ube3a^m?/p+ mice were severely impaired in initial acquisition of lever pressing. Whereas the lever pressing of wild‐type controls was reduced by outcome devaluation and instrumental contingency reversal, the performance of Ube3a^m?/p+ mice were more habitual, impervious to changes in outcome value and action–outcome contingency. In the DMS, but not the DLS, Ube3a^m?/p+ mice showed reduced amplitude and frequency of miniature excitatory postsynaptic currents. These results show for the first time a selective deficit in instrumental conditioning in the Ube3a deficient mouse model, and suggest a specific impairment in glutmatergic transmission in the associative corticostriatal circuit in AS.     

Sendai virus vector-mediated brain-derived neurotrophic factor expression ameliorates memory deficits and synaptic degeneration in a transgenic mouse model of Alzheimer's disease

Growing evidence suggests that decreased brain-derived neurotrophic factor (BDNF) levels are associated with Alzheimer's disease (AD) pathogenesis. Therefore, BDNF gene therapy is considered to be a promising therapeutic strategy for treating AD. Sendai virus (SeV) is a type I parainfluenza virus that does not interact with host chromosomes because of its strict cytoplasmic life cycle. Although SeV is nonpathogenic in primates, including humans, its infectivity for neurons is strong. Here we demonstrate that SeV vectors effectively infected neurons, even though they were injected into subcortical white matter. Moreover, SeV vectors significantly induced BDNF expression, ameliorating synaptic degeneration and memory deficits in a transgenic mouse model of AD (Tg2576). This is the first study to demonstrate that viral vector administration in white matter is sufficient to restore cognitive function in vivo. These results also support the feasibility of using SeV vectors for gene therapy targeting the brain.     

Psychiatric examination of all eight adult males with the karyotype 46,XX diagnosed in Denmark till 1976.

Psychiatric examination has been made in all eight adult males with the karyotype 46,XX diagnosed in Denmark til 1976. Apart from emotional immaturity in most probands, no psychopathological traits were found, except in one who had neurotic symptoms. They were all of normal intelligence and socially well adjusted. All had male psychosexual orientation, but weak sexual libido and potency were found in the oldest probands. In several respects males with 46,XX differ from Klinefelter males with the karyotype 47,XXY, and the reasons for this are discussed.     

Some morphometric observations on the cerebral cortex and hippocampus in presenile Alzheimer's disease, senile dementia of Alzheimer type and Down's syndrome in middle age

The frequency of senile plaques and neurofibrillary tangles and the number of pyramidal neurones and the volume of their nucleolus were measured in temporal cortex (middle temporal gyrus) and hippocampus (area h1) of 32 patients with Alzheimer's disease. Plaques and tangles were greatly increased in frequency in these patients while the pyramidal cell number was reduced (due to the effects of ageing plus disease) by a total of 78% in temporal cortex and 60% in hippocampus with nucleolar volume in surviving cells being reduced in total by 56% and 63%, respectively. These total losses did not correlate with patient age. However, when corrections for the effects of ageing alone were made on these total losses, the extent of pyramidal cell loss and decrease in nucleolar volume due solely to disease as well as the frequency of plaques and tangles were all found to correlate inversely with patient age for temporal cortex; in hippocampus only cell loss so related. The extent of nerve cell loss correlated with the reduction in nucleolar volume in temporal cortex but not in hippocampus. Correlations involving nerve cell loss and decreased nucleolar volume with plaque and tangle frequency were either weak or non-significant in both regions. The number of nerve cells and the volume of their nucleolus were less (when compared with age-matched control patients) in both temporal cortex and hippocampus, in the 6 middle aged patients with Down's syndrome, and match the corresponding values seen in 8 patients of similar age with Alzheimer's disease.     

Effects of neural stem cells on synaptic proteins and memory in a mouse model of Alzheimer's disease

Transplanting neural stem cells (NSC) to the damaged brain has been regarded as a potential treatment for neurodegenerative diseases such as Alzheimer's disease (AD), a condition characterized by memory loss. We hypothesized that transplantation of NSC into the hippocampal regions of APP + PS1 transgenic (Tg) mice, a well‐established model of AD, would enhance the expression of synaptic proteins, which may be helpful for improving cognitive function. Our results showed that NSC transplantation significantly improved spatial learning and memory function in Tg mice. The results obtained by real‐time RT‐PCR, immunofluorescence, and Western blot analyses demonstrated that the expression of synaptophysin (SYN) and that of growth‐associated protein‐43 (GAP‐43) in Tg‐NSC mice, 8 weeks after transplantation, were significantly improved compared with what was observed in Tg‐Veh (control) mice. This finding was confirmed by the increase in the number of synapses in Tg‐NSC mice as observed via electron microscopy. Our results suggest that NSC‐induced changes can recover memory loss in APP + PS1 transgenic mice, possibly by establishing new neural circuits resulting from the engrafted NSC. © 2013 Wiley Periodicals, Inc.     

白桦脂醇对APP/PS1双转基因痴呆模型小鼠认知及海马突触功能相关蛋白表达的影响

目的 探讨白桦脂醇对阿尔茨海默病（AD）小鼠的学习记忆功能的干预作用及海马突触功能相关蛋白表达的影响,为探索治疗AD提供新的可能。方法 采用白桦脂醇干预APP/PS1双转基因痴呆模型小鼠,将小鼠随机分为模型组、药物高剂量组和低剂量组,C57BL/6J健康小鼠为对照组。通过行为学观察学习记忆能力、在体电生理记录海马神经元的生物电、TUNEL法检测神经元凋亡、Realtime PCR法检测PSD-95和Synapsin-I水平。结果 水迷宫检测结果发现白桦脂醇能改善模型小鼠认知功能障碍;电生理检测AD模型组长时程增强（LTP）幅值低于对照组,经过白桦脂醇干预治疗后,白桦脂醇各组LTP幅值较AD模型组升高;AD模型组神经元凋亡率显著高于对照组,经过白桦脂醇干预治疗后凋亡率下降;AD小鼠模型海马区PSD-95和Synapsin-I表达下降,但经白桦脂醇干预后其表达上升。结论 白桦脂醇通过使海马PSD-95和Synapsin-I的表达增加,发挥对APP/PS1双转基因痴呆模型小鼠认知功能的保护,使海马长时程增强。     

Post-training excitotoxic lesions of the dorsal hippocampus attenuate forward trace,backward trace,and delay fear conditioning in a temporally specific manner

The present study sought to determine whether post-training excitotoxic lesions of the dorsal hippocampus would disrupt retention of fear conditioned using a trace procedure. Rats were trained using one of six procedures. Forward trace conditioning consisted of 10 trials in which a 16-s tone conditional stimulus (CS) was followed by a 28-s stimulus-free trace interval and then a mild footshock unconditional stimulus (US). We used two forms of delay conditioning where the tone and footshock co-terminated. Short delay used a 16-s tone and long delay used a 46-s tone. Backward trace conditioning was the same as forward trace, except that the order of the CS and US was reversed. CS-only and US-only were similar to forward trace except that the footshock or tone, respectively, was eliminated. One day later, animals received either an N-methyl-D-aspartate (NMDA)-induced lesion of the dorsal hippocampus or sham surgery. One week later, the rats were tested for freezing to the tone in a novel context. The next day, they were tested for freezing to the original training context. Hippocampal lesioned trace conditioned rats showed significantly less freezing during the tone compared with their sham lesioned controls. The lesion did not affect freezing during the tone in delay conditioning, nor in the other training conditions. During the 1-min period after tone offset, there was a trend in all hippocampal lesioned animals toward a deficit in freezing, compared with their corresponding sham lesioned controls, although only short delay, forward and backward trace groups showed a significant deficit. Hippocampal lesions also attenuated contextual conditioning. Thus, the hippocampus is critical for the consolidation and/or expression of a trace fear conditioned stimulus.     

Slow IPSC kinetics, low levels of alpha1 subunit expression and paired-pulse depression are distinct properties of neonatal inhibitory GABAergic synaptic connections in the mouse superior colliculus.

Remodelling of visual maps in the superior colliculus (SC) depends on neuronal activity. Synaptic inhibition could contribute to this process because spontaneous spike discharge in the SC was modulated by GABA(A) receptor activation at postnatal days (P) 1-3. To investigate the functional capacity of GABAergic synaptic transmission at this early stage of development, whole-cell patch-clamp recordings were made from wide field neurons (WFNs) in horizontal slices comprising the superficial grey layer of the SC. Focal stimulation in the vicinity of WFNs evoked tetrodotoxin-sensitive stimulus-locked inhibitory postsynaptic currents (eIPSCs). The failure rate of eIPSCs was low ( approximately 0.2), and the maximal amplitude of evoked unitary eIPSCs exceeded the amplitude of average miniature IPSCs (mIPSCs) by a factor of 4-5, suggesting that action potential-mediated GABA release was more effective than spontaneous release. Some of the properties of GABAergic synaptic transmission in the neonatal SC were age-specific. In contrast with eIPSCs in the more mature SC at P20-22, neonatal eIPSCs decayed more slowly, preferentially fluctuated in duration, not amplitude, and mostly lacked temporal summation, due to depression at shorter intervals. The paired-pulse ratio (eIPSC2 : eIPSC1) was inversely related to the duration of eIPSCs. PCR analysis showed, in addition, that the ratio of alpha1 : alpha3 subunit expression was lower in the neonatal SC. Together, these results suggest that, at a young age, efficacy of GABAergic synaptic transmission is primarily constrained by the slow kinetics and the saturation of postsynaptic GABA(A) receptors.     

Axospinous synaptic subtype‐specific differences in structure,size, ionotropic receptor expression,and connectivity in apical dendritic regions of rat hippocampal CA1 pyramidal neurons

The morphology of axospinous synapses and their parent spines varies widely. Additionally, many of these synapses are contacted by multiple synapse boutons (MSBs) and show substantial variability in receptor expression. The two major axospinous synaptic subtypes are perforated and nonperforated, but there are several subcategories within these two classes. The present study used serial section electron microscopy to determine whether perforated and nonperforated synaptic subtypes differed with regard to their distribution, size, receptor expression, and connectivity to MSBs in three apical dendritic regions of rat hippocampal area CA1: the proximal and distal thirds of stratum radiatum, and the stratum lacunosum‐moleculare. All synaptic subtypes were present throughout the apical dendritic regions, but there were several subclass‐specific differences. First, segmented, completely partitioned synapses changed in number, proportion, and α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionate (AMPA) receptor expression with distance from the soma beyond that found within other perforated synaptic subtypes. Second, atypically large, nonperforated synapses showed N‐methyl‐D ‐aspartate (NMDA) receptor immunoreactivity identical to that of perforated synapses, levels of AMPA receptor expression intermediate to that of nonperforated and perforated synapses, and perforated synapse‐like changes in structure with distance from the soma. Finally, MSB connectivity was highest in the proximal stratum radiatum, but only for those MSBs composed of nonperforated synapses. The immunogold data suggest that most MSBs would not generate simultaneous depolarizations in multiple neurons or spines, however, because the vast majority of MSBs are comprised of two synapses with abnormally low levels of receptor expression, or involve one synapse with a high level of receptor expression and another with only a low level. J. Comp. Neurol. 512:399–418, 2009. © 2008 Wiley‐Liss, Inc.     

QUALIDEM: development and evaluation of a dementia specific quality of life instrument. Scalability, reliability and internal structure

OBJECTIVE: To develop a Quality of Life questionnaire rated by professionals that can be used for people with dementia in different stages of the disease, living in residential settings. METHOD: Development was performed in two phases: item generation and pilot testing, and a field survey to evaluate the psychometric properties. For unidimensionality we used a non-parametric model from item response theory: the Mokken scaling model, and computed the corresponding scalability coefficients, using a theory driven strategy. RESULTS: The pilot survey resulted in a list of 49 items. The field survey was performed in a sample of 238 people with dementia residing in ten nursing homes. The scalability of the subscales positive affect, negative affect, restless tense behavior, and social relations is strong (0.50 < H < 0.63); for care relationship, positive self image, feeling at home, and having something to do, scalability was moderate (0.40 < H < 0.49), and for social isolation it was weak (H = 0.34). The reliability coefficient Rho (under assumption of double monotonicity) varied from 0.60 for social isolation to 0.90 for positive affect (Cronbach's alpha varied from 0.59 to 0.89). Twenty-one of 40 items are suited for people with very severe dementia. CONCLUSION: The QUALIDEM is an easy to administer and sufficiently reliable rating scale that provides a QOL profile of persons with dementia in residential settings. The QUALIDEM can be used for evaluation as well as for research and practice innovation.     

Fluoxetine delays the cognitive function decline and synaptic changes in a transgenic mouse model of early Alzheimer's disease

Alzheimer's disease (AD) is a progressive neurodegenerative disorder associated with cognitive decline. Previous studies have reported that the syndrome of AD begins with subtle alterations in hippocampal synapses prior to frank neuronal degeneration. It has recently been reported that fluoxetine (FLX) shows positive effects on AD patients who have depression and anxiety. However, it is unclear whether FLX can affect the pathogenesis of AD mice in the early stage of AD. To address this question, 8-month-old male APP/PS1 double-transgenic AD mice were administered a 10-week course of FLX (10 mg/kg/day) injections. Then, spatial learning and memory were evaluated using a Morris water maze test. Immunohistological staining and an unbiased stereological method were used to estimate the total number of dendritic spine synapses in the hippocampus. We found that FLX significantly shortened the mean escape latencies of the 10-month-old mice; reduced the elevated levels of soluble Aβ40, Aβ42, and amyloid plaques in the hippocampus; and prevented the decrease in dendritic spine synapses and in postsynaptic protein PSD-95 density in the dentate gyrus, CA1/2 and CA3 regions of the hippocampus. Our results indicate that reversing synaptic impairment might be considered a promising therapeutic approach for alleviating the cognitive deficits associated with early AD. Moreover, our results suggest that FLX may be a safe and effective drug for delaying the progress of AD, which might provide a starting point for further research into new preventative measures and treatments for AD.     

Survival time, mortality, and cause of death in elderly patients with Parkinson's disease: a 9-year follow-up.

This community-based study of Parkinson's disease (PD) investigated age at death and cause of death in a cohort of 170 previously studied patients. The current study is a 9-year follow-up, and the results are compared to 510 sex- and age-matched controls from the same area. A total of 170 patients were diagnosed with PD on August 31, 1989, within a defined area of Sweden. A control group of 510 persons from the same area and with the same age and sex distribution was also examined regarding age at death and cause of death. After 9.4 years, 121 cases (71.1%) and 229 controls (44.9%) were no longer alive. Thus, the mortality rate ratio was 1.6 (95% confidence interval [CI], 1.3-1.8) when comparing PD patients with controls. The all-cause hazard ratio for cases compared to controls was 2.4 (95% CI, 1.9-3.0). The mean age at death for the cases was 81.9 (95% CI, 80.3-83.0) years and for the controls 82.9 (95% CI, 82.0-83.7) years. Survival analysis also showed a shorter survival time (P < 0.001) for PD patients. Only 53% of the death certificates for the deceased patients recorded PD as an underlying or contributory cause of death. Many PD patients reached a high age but had a shorter survival than the controls. There was a significant increase in deaths from pneumonia.     

Abnormal expression of the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) in hippocampus, frontal cortex, and substantia nigra of Ts65Dn mouse: a model of Down syndrome

Ts65Dn, a mouse model of Down syndrome (DS), demonstrates abnormal hippocampal synaptic plasticity and behavioral abnormalities related to spatial learning and memory. The molecular mechanisms leading to these impairments have not been identified. In this study, we focused on the G-protein-activated inwardly rectifying potassium channel 2 (GIRK2) gene that is highly expressed in the hippocampus region. We studied the expression pattern of GIRK subunits in Ts65Dn and found that GIRK2 was overexpressed in all analyzed Ts65Dn brain regions. Interestingly, elevated levels of GIRK2 protein in the Ts65Dn hippocampus and frontal cortex correlated with elevated levels of GIRK1 protein. This suggests that heteromeric GIRK1-GIRK2 channels are overexpressed in Ts65Dn hippocampus and frontal cortex, which could impair excitatory input and modulate spike frequency and synaptic kinetics in the affected regions. All GIRK2 splicing isoforms examined were expressed at higher levels in the Ts65Dn in comparison to the diploid hippocampus. The pattern of GIRK2 expression in the Ts65Dn mouse brain revealed by in situ hybridization and immunohistochemistry was similar to that previously reported in the rodent brain. However, in the Ts65Dn mouse a strong immunofluorescent staining of GIRK2 was detected in the lacunosum molecular layer of the CA3 area of the hippocampus. In addition, tyrosine hydroxylase containing dopaminergic neurons that coexpress GIRK2 were more numerous in the substantia nigra compacta and ventral tegmental area in the Ts65Dn compared to diploid controls. In summary, the regional localization and the increased brain levels coupled with known function of the GIRK channel may suggest an important contribution of GIRK2 containing channels to Ts65Dn and thus to DS neurophysiological phenotypes.     

The role of the dorsal raphe nucleus in the development,expression, and treatment of L‐dopa‐induced dyskinesia in hemiparkinsonian rats

Convergent evidence indicates that in later stages of Parkinson's disease raphestriatal serotonin neurons compensate for the loss of nigrostriatal dopamine neurons by converting and releasing dopamine derived from exogenous administration of the pharmacotherapeutic L‐3,4‐dihydroxyphenyl‐L ‐alanine (L ‐dopa). Because the serotonin system is not equipped with dopamine autoregulatory mechanisms, it has been postulated that raphe‐mediated striatal dopamine release may fluctuate dramatically. These fluctuations may portend the development of abnormal involuntary movements called L ‐dopa‐induced dyskinesia (LID). As such, it has been hypothesized that reducing the activity of raphestriatal neurons could dampen supraphysiological stimulation of striatal dopamine receptors thereby alleviating LID. To directly address this, the current study employed the rodent model of LID to investigate the contribution of the rostral raphe nuclei (RRN) in the development, expression and treatment of LID. In the first study, dual serotonin/dopamine selective lesions of the RRN and medial forebrain bundle, respectively, verified that the RRN are essential for the development of LID. In a direct investigation into the neuroanatomical specificity of these effects, microinfusions of ±8‐OH‐DPAT into the intact dorsal raphe nucleus dose‐dependently attenuated the expression of LID without affecting the antiparkinsonian efficacy of L ‐dopa. These current findings reveal the integral contribution of the RRN in the development and expression of LID and implicate a prominent role for dorsal raphe 5‐HT1AR in the efficacious properties of 5‐HT1AR agonists. Synapse 63:610–620, 2009. © 2009 Wiley‐Liss, Inc.     

Lack of association between PSA‐NCAM expression and migration in the rostral migratory stream of a Huntington's disease transgenic mouse model

Huntington's disease is a neurodegenerative autosomal disorder characterized by selective loss of striatal and cortical neurons. The mammalian brain subventricular zone contains a population of neural precursors involved in postnatal neurogenesis. These newly generated cells migrate from the subventricular zone along the rostral migratory stream and differentiate into mature olfactory bulb neurons throughout adulthood. The establishment of this pathway depends upon a variety of molecules, including polysialylated neural cell adhesion molecule (PSA‐NCAM). We used a murine model of Huntington's disease, the R6/2 transgenic mouse, and in vivo bromodeoxyuridine administration to label cells undergoing proliferation and to follow their migration along the rostral migratory stream. Bromodeoxyuridine labeling did not show any significant increase in proliferation of progenitor cells in symptomatic R6/2 mice, but migration of neuroblasts along the rostral migratory stream was significantly diminished. The decrease in neuroblast migration was not due to an alteration in the expression of PSA‐NCAM along the rostral migratory stream since immunohistochemical analysis showed no significant differences between R6/2 and wild type mice. In addition, we used Fluoro‐Jade C to evaluate apoptosis and demonstrated that the number of apoptotic cells in the rostral migratory stream is similar in affected and wild type animals, suggesting that cell death is not responsible for the differences observed in neuroblast migration. We conclude that in R6/2 mice, progenitor cells have an impaired migration in their route to the olfactory bulb, with accumulation of cells in the caudal rostral migratory stream that does not result from changes in PSA‐NCAM expression and/or cell death.     

Cellular distribution of the Fragile X mental retardation protein in the inner ear: a developmental and comparative study in the mouse,rat, gerbil,and chicken

The Fragile X mental retardation protein (FMRP) is an mRNA binding protein that is essential for neural circuit assembly and synaptic plasticity. Loss of functional FMRP leads to Fragile X syndrome (FXS), a neurodevelopmental disorder characterized by sensory dysfunction including abnormal auditory processing. While the central mechanisms of FMRP regulation have been studied in the brain, whether FMRP is expressed in the auditory periphery and how it develops and functions remains unknown. In this study, we characterized the spatiotemporal distribution pattern of FMRP immunoreactivity in the inner ear of mice, rats, gerbils, and chickens. Across species, FMRP was expressed in hair cells and supporting cells, with a particularly high level in immature hair cells during the prehearing period. Interestingly, the distribution of cytoplasmic FMRP displayed an age-dependent translocation in hair cells, and this feature was conserved across species. In the auditory ganglion (AG), FMRP immunoreactivity was detected in neuronal cell bodies as well as their peripheral and central processes. Distinct from hair cells, FMRP intensity in AG neurons was high both during development and after maturation. Additionally, FMRP was evident in mature glial cells surrounding AG neurons. Together, these observations demonstrate distinct developmental trajectories across cell types in the auditory periphery. Given the importance of peripheral inputs to the maturation of auditory circuits, these findings implicate involvement of FMRP in inner ear development as well as a potential contribution of periphery FMRP to the generation of auditory dysfunction in FXS.     

Placement,relocation and end of life issues in aging adults with and without Down's syndrome: a retrospective study

Background Aging adults with Down's syndrome (DS) experience more relocations and other life events than adults with intellectual disabilities aged 50 and older without DS. Age‐related functional decline and the higher incidence of dementia were implicated as the contributing factors that led to relocation and nursing home placement. Method A retrospective study of adults with intellectual disabilities who were born prior to the year 1946 was conducted to analyse the number of relocations experienced over a 5‐ and 10‐year period. The cohort consisted of 140 individuals (61 with DS between ages 50–71 years, and 79 without DS between ages 57–89 years) who had been referred to a diagnostic and research clinic. Results Analyses revealed the number of relocations over a 5‐ and 10‐year period were significantly greater in the DS group. Placement in a nursing home for end of life care was significantly higher in the DS group whereas the majority (90%) in the non‐DS group remained in a group home setting. Mortality was significantly earlier in the DS group with the mean age at death to be 61.4 years compared with 73.2 years in the non‐DS group. Conclusions The present results suggest that aging adults with DS encounter more relocations, and are more likely to have their final placement for end of life care in a nursing home. In contrast, the adults without DS were subjected to less relocation and remained in the same group home setting.