Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, featuring social communication deficit and repetitive/restricted behaviors as common symptoms. Its prevalence has continuously increased, but, till now, there are no therapeutic approaches to relieve the core symptoms, particularly social deficit. In previous studies, abnormal function of the glutamatergic neural system has been proposed as a critical mediator and therapeutic target of ASD-associated symptoms. Here, we investigated the possible roles of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in autism symptoms using two well-known autistic animal models, Cntnap2 knockout (KO) mice and in utero valproic acid-exposed ICR (VPA) mice. We found that Cntnap2 KO mice displayed decreased glutamate receptor expression and transmission. Contrarily, VPA mice exhibited increased glutamate receptor expression and transmission. Next, we investigated whether AMPAR modulators (positive-allosteric-modulator for Cntnap2 KO mice and antagonist for VPA mice) can improve autistic symptoms by normalizing the aberrant excitatory transmission in the respective animal models. Interestingly, the AMPAR modulation specifically ameliorated social deficits in both animal models. These results indicated that AMPAR-derived excitatory neural transmission changes can affect normal social behavior. To validate this, we injected an AMPAR agonist or antagonist in control ICR mice and, interestingly, these treatments impaired only the social behavior, without affecting the repetitive and hyperactive behaviors. Collectively, these results provide insight into the role of AMPARs in the underlying pathophysiological mechanisms of ASD, and demonstrate that modulation of AMPAR can be a potential target for the treatment of social behavior deficits associated with ASD.

Longitudinal Analysis of Outpatient Physician Visits in the Oldest Old: Results of the AgeQualiDe Prospective Cohort Study.

OBJECTIVES: The aim of this study was to identify determinants of outpatient health care utilization among the oldest old in Germany longitudinally. DESIGN: Multicenter prospective cohort "Study on Needs, health service use, costs and health-related quality of life in a large sample of oldest-old primary care patients (85+)" (AgeQualiDe). SETTING: Individuals in very old age were recruited via GP offices at six study centers in Germany. The course of outpatient health care was observed over 10 months (two waves). PARTICIPANTS: Primary care patients aged 85 years and over (at baseline: n=861, with mean age of 89.0 years±2.9 years; 85-100 years). MEASUREMENTS: Self-reported numbers of outpatient visits to general practitioners (GP) and specialists in the past three months were used as dependent variables. Widely used scales were used to quantify explanatory variables (e.g., Geriatric Depression Scale, Instrumental Activities of Daily Living Scale, or Global Deterioration Scale). RESULTS: Fixed effects regressions showed that increases in GP visits were associated with increases in cognitive impairment, whereas they were not associated with changes in marital status, functional decline, increasing number of chronic conditions, increasing age, and changes in social network. Increases in specialist visits were not associated with changes in the explanatory variables. CONCLUSION: Our findings underline the importance of cognitive impairment for GP visits. Creating strategies to postpone cognitive decline might be beneficial for the health care system.

[Informal care for dementia according to type of service]. / Informelle Pflege bei Demenz nach Leistungsarten.

BACKGROUND: Dementia is a major challenge for society and its impact will grow in the future. Informal care is an essential part of dementia care. Previous studies considered informal care as a whole and not by its components. OBJECTIVE: We aimed to assess the degree of association between specific informal care services and dementia. MATERIAL AND METHODS: This analysis is based on data from the seventh wave of the AgeCoDe/AgeQualiDe study. Dementia was diagnosed based on the DSM-IV criteria. Severity of dementia was assessed and categorized by means of the Clinical Dementia Rating and eight individual informal care services were considered. Logistic regression models were used to assess associations. RESULTS: Of the 864 participants 18% suffered from dementia (very mild: 4%; mild: 6%; moderate: 5%; severe: 3%). All informal care services were significantly associated with dementia, with an emphasis on "supervision", "regulation of financial matters" and "assistance in the intake of medication". Considering different degrees of dementia severity, similar results arose from the analyses. All three aforementioned services showed a pronounced association with all degrees of dementia severity, except for supervision and very mild dementia. CONCLUSION: The provision of all types of informal care services is associated with dementia. The association is pronounced for services that can be more easily integrated into the daily routines of the informal caregiver. Policy makers who plan to integrate informal care into the general care arrangements for dementia should consider this.

Effects of Several Cosmetic Preservatives on ROS-Dependent Apoptosis of Rat Neural Progenitor Cells.

Benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea are commonly used preservatives in cosmetics. Recent reports suggested that these compounds may have cellular and systemic toxicity in high concentration. In addition, diazolidinyl urea and imidazolidinyl urea are known formaldehyde (FA) releasers, raising concerns for these cosmetic preservatives. In this study, we investigated the effects of benzalkonium chloride, diazolidinyl urea, and imidazolidinyl urea on ROS-dependent apoptosis of rat neural progenitor cells (NPCs) in vitro. Cells were isolated and cultured from embryonic day 14 rat cortices. Cultured cells were treated with 1-1,000 nM benzalkonium chloride, and 1-50 µM diazolidinyl urea or imidazolidinyl urea at various time points to measure the reactive oxygen species (ROS). PI staining, MTT assay, and live-cell imaging were used for cell viability measurements. Western blot was carried out for cleaved caspase-3 and cleaved caspase-8 as apoptotic protein markers. In rat NPCs, ROS production and cleaved caspase-8 expression were increased while the cell viability was decreased in high concentrations of these substances. These results suggest that several cosmetic preservatives at high concentrations can induce neural toxicity in rat brains through ROS induction and apoptosis.

T-Type Calcium Channels Are Required to Maintain Viability of Neural Progenitor Cells.

T-type calcium channels are low voltage-activated calcium channels that evoke small and transient calcium currents. Recently, T-type calcium channels have been implicated in neurodevelopmental disorders such as autism spectrum disorder and neural tube defects. However, their function during embryonic development is largely unknown. Here, we investigated the function and expression of T-type calcium channels in embryonic neural progenitor cells (NPCs). First, we compared the expression of T-type calcium channel subtypes (CaV3.1, 3.2, and 3.3) in NPCs and differentiated neural cells (neurons and astrocytes). We detected all subtypes in neurons but not in astrocytes. In NPCs, CaV3.1 was the dominant subtype, whereas CaV3.2 was weakly expressed, and CaV3.3 was not detected. Next, we determined CaV3.1 expression levels in the cortex during early brain development. Expression levels of CaV3.1 in the embryonic period were transiently decreased during the perinatal period and increased at postnatal day 11. We then pharmacologically blocked T-type calcium channels to determine the effects in neuronal cells. The blockade of T-type calcium channels reduced cell viability, and induced apoptotic cell death in NPCs but not in differentiated astrocytes. Furthermore, blocking T-type calcium channels rapidly reduced AKT-phosphorylation (Ser473) and GSK3ß-phosphorylation (Ser9). Our results suggest that T-type calcium channels play essential roles in maintaining NPC viability, and T-type calcium channel blockers are toxic to embryonic neural cells, and may potentially be responsible for neurodevelopmental disorders.

Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development.

The valproic acid (VPA)-induced animal model is one of the most widely utilized environmental risk factor models of autism. Autism spectrum disorder (ASD) remains an insurmountable challenge among neurodevelopmental disorders due to its heterogeneity, unresolved pathological pathways and lack of treatment. We previously reported that VPA-exposed rats and cultured rat primary neurons have increased Pax6 expression during post-midterm embryonic development which led to the sequential upregulation of glutamatergic neuronal markers. In this study, we provide experimental evidence that telomerase reverse transcriptase (TERT), a protein component of ribonucleoproteins complex of telomerase, is involved in the abnormal components caused by VPA in addition to Pax6 and its downstream signals. In embryonic rat brains and cultured rat primary neural progenitor cells (NPCs), VPA induced the increased expression of TERT as revealed by Western blot, RT-PCR, and immunostainings. The HDAC inhibitor property of VPA is responsible for the TERT upregulation. Chromatin immunoprecipitation revealed that VPA increased the histone acetylation but blocked the HDAC1 binding to both Pax6 and Tert genes. Interestingly, the VPA-induced TERT overexpression resulted to sequential upregulations of glutamatergic markers such as Ngn2 and NeuroD1, and inter-synaptic markers such as PSD-95, α-CaMKII, vGluT1 and synaptophysin. Transfection of Tert siRNA reversed the effects of VPA in cultured NPCs confirming the direct involvement of TERT in the expression of those markers. This study suggests the involvement of TERT in the VPA-induced autistic phenotypes and has important implications for the role of TERT as a modulator of balanced neuronal development and transmission in the brain.

Does Visual Impairment Affect Social Ties in Late Life? Findings of a Multicenter Prospective Cohort Study in Germany.

OBJECTIVE: To investigate how visual impairment affects social ties in late life longitudinally. DESIGN: Population-based prospective cohort study. SETTING: Individuals in old age were recruited via general practitioners' offices (at six study centers) in Germany. They were interviewed every 18 months. PARTICIPANTS: Individuals aged 75 years and above at baseline. Follow-up wave 2 (36 months after baseline, n=2,443) and wave 4 (72 months after baseline, n=1,618) were used for the analyses presented here. MEASUREMENTS: Social ties were assessed using the 14-item form of the questionnaire for social support (F-SozU K-14). Visual impairment was self-rated on a three level Likert scale (no impairment, mild visual impairment, or severe/profound visual impairment). RESULTS: Adjusting for sociodemographic factors, hearing impairment and comorbidity, fixed effects regressions revealed that the onset of mild visual impairment decreased the social support score, in particular the emotional support score. Additionally, the onset of mild hearing impairment decreased the social support score in men. Moreover, increasing age decreased the social support score in the total sample and in both sexes. Loss of spouse and increasing comorbidity did not affect the social support score. CONCLUSION: Our results highlight the importance of visual impairment for social ties in late life. Consequently, appropriate strategies in order to delay visual impairment might help to maintain social ties in old age.

Factors Affecting Functional Impairment among Elderly Germans - Results of a Longitudinal Study.

OBJECTIVE: To investigate causal factors of functional impairment in old age in a longitudinal approach. DESIGN: A population-based prospective cohort study. SETTING: Elderly individuals were recruited via GP offices at six study centers in Germany. They were observed every 1.5 years over six waves. PARTICIPANTS: Three thousand two hundred fifty-six people aged 75 years and older at baseline. MEASUREMENTS: Functional impairment was quantified by the Lawton and Brody Instrumental Activities of Daily Living scale (IADL) and the Barthel-Index (BI). RESULTS: Fixed effects regressions revealed that functional impairment (IADL; BI) increased significantly with ageing (ß=-.2; ß=-1.1), loss of a spouse (ß= .5; ß=-3.1), not living alone in private household (ß=-1.2; ß=-5.5), depression (solely significant for IADL: ß= .6) and dementia (ß=-2.3; ß=-18.2). The comorbidity score did not affect functional impairment. CONCLUSION: Our findings underline the relevance of changes in sociodemographic variables as well as the occurrence of depression or dementia for functional impairment. While several of these causal factors for functional decline in the oldest old are inevitable, some may not be, such as depression. Therefore, developing interventional strategies to prevent depression might be a fruitful approach in order to delay functional impairment in old age.

[Longitudinal Predictors of the Need for Care]. / Einflussfaktoren auf die Pflegebedürftigkeit im Längsschnitt.

Background: Little is known about the longitudinal predictors of the need for care in old age. However, the knowledge of these factors is important for developing strategies for prevention or delay the need for care. Thus, we aimed at investigating the factors affecting the need for care in old age. Methods: In this population-based prospective cohort study (AgeCoDe, with n=3 217 individuals aged 75 years and above at baseline), the need for care was observed over 4.5 years. The need for care was quantified by the care level defined by the German Law (§ 15 SGB XI). Longitudinal predictors (sociodemographic variables, impairment in mobility/hearing/vision, dementia and depression) of the need for care were examined by using Random Effects Logit regressions. Results: Longitudinal regression analysis revealed that the probability of the need for care significantly increased with the occurrence of dementia (OR: 48.2), mobility impairments (aggravated walking, OR: 26.4; disability of walking, OR: 747.9) and age (e. g. 90 years and above vs.<80 years, OR: 32.3). The influence of family status, living conditions, visual impairment and depression on need for care was markedly smaller, and the effect of hearing impairments did not achieve statistical significance. Conclusion: In order to prevent or delay the need for care in old age, treatments should aim at preserving mobility and cognition. Due to demographic ageing, developing such programs is of major importance for health policy.

Erratum: Valproic Acid Induces Telomerase Reverse Transcriptase Expression during Cortical Development.

[This corrects the article on p. 252 in vol. 26, PMID: 29093634.].

Agmatine rescues autistic behaviors in the valproic acid-induced animal model of autism.

Autism spectrum disorder (ASD) is an immensely challenging developmental disorder characterized primarily by two core behavioral symptoms of social communication deficits and restricted/repetitive behaviors. Investigating the etiological process and identifying an appropriate therapeutic target remain as formidable challenges to overcome ASD due to numerous risk factors and complex symptoms associated with the disorder. Among the various mechanisms that contribute to ASD, the maintenance of excitation and inhibition balance emerged as a key factor to regulate proper functioning of neuronal circuitry. Interestingly, our previous study involving the valproic acid animal model of autism (VPA animal model) has demonstrated excitatory-inhibitory imbalance (E/I imbalance) due to enhanced differentiation of glutamatergic neurons and reduced GABAergic neurons. Here, we investigated the potential of agmatine, an endogenous NMDA receptor antagonist, as a novel therapeutic candidate in ameliorating ASD symptoms by modulating E/I imbalance using the VPA animal model. We observed that a single treatment of agmatine rescued the impaired social behaviors as well as hyperactive and repetitive behaviors in the VPA animal model. We also observed that agmatine treatment rescued the overly activated ERK1/2 signaling in the prefrontal cortex and hippocampus of VPA animal models, possibly, by modulating over-excitability due to enhanced excitatory neural circuit. Taken together, our results have provided experimental evidence suggesting a possible therapeutic role of agmatine in ameliorating ASD-like symptoms in the VPA animal model of ASD.

Predictors of Frailty in Old Age - Results of a Longitudinal Study.

OBJECTIVES: To investigate time-dependent predictors of frailty in old age longitudinally. DESIGN: Population-based prospective cohort study. SETTING: Elderly individuals were recruited via GP offices at six study centers in Germany. The course of frailty was observed over 1.5 years (follow up wave 4 and follow up wave 5). PARTICIPANTS: 1,602 individuals aged 80 years and older (mean age 85.4 years SD 3.2, with mean CSHA CFS 3.5 SD 1.6) at follow up wave 4. MEASUREMENTS: Frailty was assessed by using the Canadian Study of Health and Aging Clinical Frailty Scale (CSHA CFS), ranging from 1 (very fit) to 7 (severely frail). RESULTS: Fixed effects regressions revealed that frailty increased significantly with increasing age (ß=.2) as well as the occurrence of depression (ß=.5) and dementia (ß=.8) in the total sample. Changes in marital status and comorbidity did not affect frailty. While the effects of depression and dementia were significant in women, these effects did not achieve statistical significance in men. CONCLUSION: Our findings highlight the role of aging as well as the occurrence of dementia and depression for frailty. Specifically, in order to delay frailty in old age, developing interventional strategies to prevent depression might be a fruitful approach.

Supplementation of Korean Red Ginseng improves behavior deviations in animal models of autism.

BACKGROUND: Autism spectrum disorder (ASD) is heterogeneous neurodevelopmental disorders that primarily display social and communication impairments and restricted/repetitive behaviors. ASD prevalence has increased in recent years, yet very limited therapeutic targets and treatments are available to counteract the incapacitating disorder. Korean Red Ginseng (KRG) is a popular herbal plant in South Korea known for its wide range of therapeutic effects and nutritional benefits and has recently been gaining great scientific attention, particularly for its positive effects in the central nervous system. OBJECTIVES: Thus, in this study, we investigated the therapeutic potential of KRG in alleviating the neurobehavioral deficits found in the valproic acid (VPA)-exposed mice models of ASD. DESIGN: Starting at 21 days old (P21), VPA-exposed mice were given daily oral administrations of KRG solution (100 or 200 mg/kg) until the termination of all experiments. From P28, mice behaviors were assessed in terms of social interaction capacity (P28-29), locomotor activity (P30), repetitive behaviors (P32), short-term spatial working memory (P34), motor coordination (P36), and seizure susceptibility (P38). RESULTS: VPA-exposed mice showed sociability and social novelty preference deficits, hyperactivity, increased repetitive behavior, impaired spatial working memory, slightly affected motor coordination, and high seizure susceptibility. Remarkably, long-term KRG treatment in both dosages normalized all the ASD-related behaviors in VPA-exposed mice, except motor coordination ability. CONCLUSION: As a food and herbal supplement with various known benefits, KRG demonstrated its therapeutic potential in rescuing abnormal behaviors related to autism caused by prenatal environmental exposure to VPA.

[Prevention of Alzheimer's dementia in Germany : A projection of the possible potential of reducing selected risk factors]. / Prävention von Alzheimer-Demenz in Deutschland : Eine Hochrechnung des möglichen Potenzials der Reduktion ausgewählter Risikofaktoren.

BACKGROUND: Current international projections suggest that reducing the prevalence of seven well-established risk factors, midlife hypertension and obesity, diabetes mellitus, depression, physical inactivity, smoking and low educational attainment, may also substantially reduce the prevalence of Alzheimer's dementia (AD). OBJECTIVE: Following the procedures of the international projections, in this study we aimed to provide projections of a corresponding potential for prevention specific for Germany. METHODS: For each risk factor separately and combined (with adjustment for the association between the risk factors) we calculated (1) the population attributable risk (PAR) for AD, (2) the corresponding total number of attributable AD cases and (3) the potential number of current AD cases that may have been prevented by a 10 %, 25 % and 50 % lower prevalence of the risk factors. RESULTS: According to the population projections 30.5 % of the current AD cases in Germany could be attributable to the risk factors considered (305,000 AD cases in total). The highest estimated impact on AD prevalence was found for physical inactivity (PAR = 21.7 %, 217,000 attributable cases) and smoking (PAR = 14.9 %, 149,000 cases). A 10-50 % reduction in the prevalence of all seven risk factors could have potentially prevented 23,000-130,000 of the current AD cases in Germany. CONCLUSION: The identified possible substantial potential for reducing AD prevalence should act as a strong additional incentive to reduce the seven risk factors in Germany.

Effects of Triclosan on Neural Stem Cell Viability and Survival.

Triclosan is an antimicrobial or sanitizing agent used in personal care and household products such as toothpaste, soaps, mouthwashes and kitchen utensils. There are increasing evidence of the potentially harmful effects of triclosan in many systemic and cellular processes of the body. In this study, we investigated the effects of triclosan in the survivability of cultured rat neural stem cells (NSCs). Cortical cells from embryonic day 14 rat embryos were isolated and cultured in vitro. After stabilizing the culture, triclosan was introduced to the cells with concentrations ranging from 1 µM to 50 µM and in varied time periods. Thereafter, cell viability parameters were measured using MTT assay and PI staining. TCS decreased the cell viability of treated NSC in a concentration-dependent manner along with increased expressions of apoptotic markers, cleaved caspase-3 and Bax, while reduced expression of Bcl2. To explore the mechanisms underlying the effects of TCS in NSC, we measured the activation of MAPKs and intracellular ROS. TCS at 50 µM induced the activations of both p38 and JNK, which may adversely affect cell survival. In contrast, the activities of ERK, Akt and PI3K, which are positively correlated with cell survival, were inhibited. Moreover, TCS at this concentration augmented the ROS generation in treated NSC and depleted the glutathione activity. Taken together, these results suggest that TCS can induce neurodegenerative effects in developing rat brains through mechanisms involving ROS activation and apoptosis initiation.

Exploring the Validity of Valproic Acid Animal Model of Autism.

The valproic acid (VPA) animal model of autism spectrum disorder (ASD) is one of the most widely used animal model in the field. Like any other disease models, it can't model the totality of the features seen in autism. Then, is it valid to model autism? This model demonstrates many of the structural and behavioral features that can be observed in individuals with autism. These similarities enable the model to define relevant pathways of developmental dysregulation resulting from environmental manipulation. The uncovering of these complex pathways resulted to the growing pool of potential therapeutic candidates addressing the core symptoms of ASD. Here, we summarize the validity points of VPA that may or may not qualify it as a valid animal model of ASD.

High sucrose consumption during pregnancy induced ADHD-like behavioral phenotypes in mice offspring.

In recent years, the average consumption of sugar in humans from all ages has remarkably increased, exceeding the recommended limit. Pregnancy is a critical time for the global development of offsprings who are vulnerable to the deleterious effects of environmental factors. In this study, we investigated whether high sucrose consumption during pregnancy could affect the attention-deficit hyperactivity disorder (ADHD)-like neurobehavioral outcomes in offspring mice. Pregnant mice were randomly grouped and orally administered with either water as control (Con) or 30% wt/vol sucrose diluted in water at 6 (Suc6) or 9 (Suc9) g/kg dosage per day from gestational days 6 to 15. After the weaning period, offspring mice underwent a series of behavioral testing for locomotor activity, attention, and impulsivity. Although there is no obvious difference in gross development of offspring mice such as weight gain, high sucrose-exposed offspring mice showed a significantly increased locomotor activity. Moreover, these mice exhibited a dose-dependent decrease in attention and increase in impulsivity. In the striatum, a significantly increased dopamine transporter (DAT) mRNA expression was found in the Suc9 group along with dose-dependent decreases in the Drd1, Drd2 and Drd4 dopamine receptor subtypes. Furthermore, synaptosomal DAT protein expression was increased about twofold in the Suc9 group. Prenatal fructose exposure also induced hyperactive behavior in offspring mice suggesting the essential role of fructose in the dysregulated neurobehavioral development. These findings suggest prenatal sucrose consumption as a new risk factor for ADHD, which may need further attention and investigation in humans.

Mortality in incident dementia - results from the German Study on Aging, Cognition, and Dementia in Primary Care Patients.

OBJECTIVE: Dementia is known to increase mortality, but the relative loss of life years and contributing factors are not well established. Thus, we aimed to investigate mortality in incident dementia from disease onset. METHOD: Data were derived from the prospective longitudinal German AgeCoDe study. We used proportional hazards models to assess the impact of sociodemographic and health characteristics on mortality after dementia onset, Kaplan-Meier method for median survival times. RESULTS: Of 3214 subjects at risk, 523 (16.3%) developed incident dementia during a 9-year follow-up period. Median survival time after onset was 3.2 years (95% CI = 2.8-3.7) at a mean age of 85.0 (SD = 4.0) years (≥2.6 life years lost compared with the general German population). Survival was shorter in older age, males other dementias than Alzheimer's, and in the absence of subjective memory complaints (SMC). CONCLUSION: Our findings emphasize that dementia substantially shortens life expectancy. Future studies should further investigate the potential impact of SMC on mortality in dementia.

Repeated neonatal propofol administration induces sex-dependent long-term impairments on spatial and recognition memory in rats.

Propofol is an anesthetic agent that gained wide use because of its fast induction of anesthesia and rapid recovery post-anesthesia. However, previous studies have reported immediate neurodegeneration and long-term impairment in spatial learning and memory from repeated neonatal propofol administration in animals. Yet, none of those studies has explored the sex-specific long-term physical changes and behavioral alterations such as social (sociability and social preference), emotional (anxiety), and other cognitive functions (spatial working, recognition, and avoidance memory) after neonatal propofol treatment. Seven-day-old Wistar-Kyoto (WKY) rats underwent repeated daily intraperitoneal injections of propofol or normal saline for 7 days. Starting fourth week of age and onwards, rats were subjected to behavior tests including open-field, elevated-plus-maze, Y-maze, 3-chamber social interaction, novel-object-recognition, passive-avoidance, and rotarod. Rats were sacrificed at 9 weeks and hippocampal protein expressions were analyzed by Western blot. Results revealed long-term body weight gain alterations in the growing rats and sex-specific impairments in spatial (female) and recognition (male) learning and memory paradigms. A markedly decreased expression of hippocampal NMDA receptor GluN1 subunit in female- and increased expression of AMPA GluR1 subunit protein expression in male rats were also found. Other aspects of behaviors such as locomotor activity and coordination, anxiety, sociability, social preference and avoidance learning and memory were not generally affected. These results suggest that neonatal repeated propofol administration disrupts normal growth and some aspects of neurodevelopment in rats in a sex-specific manner.

Treatment of GABA from Fermented Rice Germ Ameliorates Caffeine-Induced Sleep Disturbance in Mice.

γ-Aminobutyric acid (GABA), a major inhibitory neurotransmitter in the mammalian central nervous system, is involved in sleep physiology. Caffeine is widely used psychoactive substance known to induce wakefulness and insomnia to its consumers. This study was performed to examine whether GABA extracts from fermented rice germ ameliorates caffeine-induced sleep disturbance in mice, without affecting spontaneous locomotor activity and motor coordination. Indeed, caffeine (10 mg/kg, i.p.) delayed sleep onset and reduced sleep duration of mice. Conversely, rice germ ferment extracts-GABA treatment (10, 30, or 100 mg/kg, p.o.), especially at 100 mg/kg, normalized the sleep disturbance induced by caffeine. In locomotor tests, rice germ ferment extracts-GABA slightly but not significantly reduced the caffeine-induced increase in locomotor activity without affecting motor coordination. Additionally, rice germ ferment extracts-GABA per se did not affect the spontaneous locomotor activity and motor coordination of mice. In conclusion, rice germ ferment extracts-GABA supplementation can counter the sleep disturbance induced by caffeine, without affecting the general locomotor activities of mice.