Effects of the Fasting-Postprandial State on Arterial Spin Labeling MRI-Based Cerebral Perfusion Quantification in Alzheimer's Disease.

BACKGROUND: The fasting-postprandial state remains an underrecognized confounding factor for quantifying cerebral blood flow (CBF) in the cognitive assessment and differential diagnosis of Alzheimer's disease (AD). PURPOSE: To investigate the effects of fasting-postprandial state on arterial spin labeling (ASL)-based CBF in AD patients. STUDY TYPE: Prospective. SUBJECTS: Ninety-two subjects (mean age = 62.5 ± 6.4 years; females 29.3%), including 30 with AD, 32 with mild cognitive impairment (MCI), and 30 healthy controls (HCs). Differential diagnostic models were developed with a 4:1 training to testing set ratio. FIELD STRENGTH/SEQUENCE: 3-T, T1-weighted imaging using gradient echo and pseudocontinuous ASL imaging using turbo spin echo. ASSESSMENT: Two ASL scans were acquired to quantify fasting state and postprandial state regional CBFs based on an automated anatomical labeling atlas. Two-way ANOVA was used to assess the effects of fasting/postprandial state and disease state (AD, MCI, and HC) on regional CBF. Pearson's correlation analysis was conducted between regional CBF and cognitive scores (Mini-Mental State Examination [MMSE] and Montreal Cognitive Assessment [MoCA]). The diagnostic performances of the fasting state, postprandial state, and mixed state (random mixing of the fasting and postprandial state CBF) in differential diagnosis of AD were conducted using support vector machine and logistic regression models. STATISTICAL TESTS: Two-way ANOVA, Pearson's correlation, and area under the curve (AUC) of diagnostic model were performed. P values <0.05 indicated statistical significance. RESULTS: Fasting-state CBF was correlated with cognitive scores in more brain regions (17 vs. 4 [MMSE] and 15 vs. 9 [MoCA]) and had higher absolute correlation coefficients than postprandial-state CBF. In the differential diagnosis of AD patients from MCI patients and HCs, fasting-state CBF outperformed mixed-state CBF, which itself outperformed postprandial-state CBF. DATA CONCLUSION: Compared with postprandial CBF, fasting-state CBF performed better in terms of cognitive score correlations and in differentiating AD patients from MCI patients and HCs. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 3.

Relation between LRG1 and CD4+ T cells, cognitive impairment and neurological function in patients with acute ischemic stroke.

Objective: To assess the relationship between LRG1 and CD4+ T cells, cognitive impairment and neurological function in acute ischemic stroke (AIS). Methods: Plasma LRG1 was detected by ELISA in 175 patients with AIS at baseline, day (D) 1, D7, month (M) 1 and M3. Results: LRG1 was negatively related to Th2 and Treg cells and positively linked to Th17 (all p < 0.05). LRG1 increased from baseline to D1, then decreased until M3 (p < 0.001). LRG1 at each assessment point was increased in patients with cognitive impairment or poor neurological function at M3 versus those without (all p < 0.05). Conclusion: LRG1 is linked to decreased Th2 and Tregs, increased Th17, cognitive impairment and nonideal neurological function recovery in patients with AIS.

Impaired neural circuitry of hippocampus in Pax2 nervous system-specific knockout mice leads to restricted repetitive behaviors.

INTRODUCTION: Restricted repetitive behaviors (RRBs), which are associated with many different neurological and mental disorders, such as obsessive-compulsive disorder (OCD) and autism, are patterns of behavior with little variation and little obvious function. Paired Box 2 (Pax2) is a transcription factor that is expressed in many systems, including the kidney and the central nervous system. The protein that is encoded by Pax2 has been implicated in the development of the nervous system and neurodevelopmental disorders. In our previous study, Pax2 heterozygous gene knockout mice (Pax2+/- mice) showed abnormally increased self-grooming and impaired learning and memory abilities. However, it remains unclear which cell type is involved in this process. In this study, we deleted Pax2 only in the nervous system to determine the regulatory mechanism of Pax2 in RRBs. METHODS: In this study, Pax2 nervous system-specific knockout mice (Nestin-Pax2 mice) aged 6-8 weeks and Pax2 flox mice of the same age were recruited as the experimental group. Tamoxifen and vehicle were administered via intraperitoneal injection to induce Pax2 knockout after gene identification. Western blotting was used to detect Pax2 expression. After that, we assessed the general health of these two groups of mice. The self-grooming test, marble burying test and T-maze acquisition and reversal learning test were used to observe the lower-order and higher-order RRBs. The three-chamber test, Y-maze, and elevated plus-maze were used to assess social ability, spatial memory ability, and anxiety. Neural circuitry tracing and transcriptome sequencing (RNA-seq) were used to observe the abnormal neural circuitry, differentially expressed genes (DEGs) and signaling pathways affected by Pax2 gene knockout in the nervous system and the putative molecular mechanism. RESULTS: (1) The Nestin-Pax2 mouse model was successfully constructed, and the Nestin-Pax2 mice showed decreased expression of Pax2. (2) Nestin-Pax2 mice showed increased self-grooming behavior and impaired T-maze reversal behavior compared with Pax2 flox mice. (3) An increased number of projection fibers can be found in the mPFC projecting to the CA1 and BLA, and a reduction in IGFBP2 can be found in the hippocampus of Nestin-Pax2 mice. CONCLUSION: The results demonstrated that loss of Pax2 in the nervous system leads to restricted repetitive behaviors. The mechanism may be associated with impaired neural circuitry and a reduction in IGFBP2.

Decreased Microglia in Pax2 Mutant Mice Leads to Impaired Learning and Memory.

Impaired learning and memory ability is one of the characteristics of a variety of neurological diseases, and its molecular mechanisms are complex and diverse and are regulated by a variety of factors. It is generally believed that synaptic plasticity plays an important role in the process of learning and memory. The protein encoded by the Pax2 gene is a transcription factor involved in neuron migration and cell fate determination during neural development. Mice knocked out of BDNF in the Pax2 lineage-derived interneuron precursor exhibited learning disabilities and severe cognitive impairment. In this study, Pax2 heterozygous gene (Pax2+/- mice) deletion mice were used as the research objects and behavioral tests were used to observe the effect of Pax2 gene deletion on learning and memory ability; morphological and molecular biological methods were used to observe the effect of Pax2 gene deletion on the neural structure. Single-cell transcriptome sequencing was used to observe the cell subtypes and differentially expressed genes (DEGs) and signaling pathways affected by Pax2 gene deletion and the possible molecular mechanisms. The results showed that Pax2+/- mice had impaired learning and memory ability, abnormal synaptic structure, and significantly reduced number of microglia clusters, and DEGs were associated with pro-inflammatory chemokines. Finally, we speculate that Pax2 gene deletion may lead to abnormal chemokines and chemokine receptors by affecting microglia.

Epothilone D Modulates Autism-like Behaviors in the BTBR Mouse Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by impaired social communication, abnormal repetitive behaviors and restricted interests and/or sensory behaviors. It has been widely accepted that ASD involves a complex interplay of both genetic and environmental risk factors. Existing medications are only symptomatic treatments, there are no effective treatments that can improve these core social behavior deficits. Recent studies indicated that synaptic development and abnormal myelination are linked to the pathogenesis of ASD. The stable tubule only polypeptide (STOP) protein, also known as microtubule-associated protein 6, plays an important role in neuronal development and synaptic plasticity. Our previous studies showed that STOP protein was significantly reduced in the plasma of autistic subjects and in the cortex of BTBR T+ Itpr3tf (BTBR) mouse model of ASD. Furthermore, studies have shown that Epothilone D, a taxol-like microtubule-stabilizing agent, could alleviate behavioral and synaptic deficits in STOP-null mice. Here, we further evaluate whether Epothilone D treatment is sufficient to modulate the autism-like behaviors in the BTBR mice, and explore the underlying mechanism. BTBR mice were treated either with Epothilone D dissolved in 99% dimethyl sulfoxide (DMSO) or with 99% DMSO vehicle. Our studies demonstrated that the restricted and repetitive behaviors of BTBR mice were improved after Epothilone D treatment, which could be achieved by improving microtubule stability and further regulating the expression of excitatory synapse-related and myelin-related proteins. These results indicate that microtubule stability may be a new and promising therapeutic target for treating patients with ASD.

The Role of PAX2 in Neurodevelopment and Disease.

In developmental biology, transcription factors are involved in regulating the process of neural development, controlling the differentiation of nerve cells, and affecting the normal functioning of neural circuits. Transcription factors regulate the expression of multiple genes at the same time and have become a key gene category that is recognized to be disrupted in neurodevelopmental disorders such as autism spectrum disorders. This paper briefly introduces the expression and role of PAX2 in neurodevelopment and discusses the neurodevelopmental disorders associated with Pax2 mutations and its possible mechanism. Firstly, mutations in the human Pax2 gene are associated with abnormalities in multiple systems which can result in neurodevelopmental disorders such as intellectual disability, epilepsy and autism spectrum disorders. Secondly, the structure of Pax2 gene and PAX2 protein, as well as the function of Pax2 gene in neural development, was discussed. Finally, a diagram of the PAX2 protein regulatory network was made and a possible molecular mechanism of Pax2 mutations leading to neurodevelopmental disorders from the perspectives of developmental process and protein function was proposed.

Increased repetitive self-grooming occurs in Pax2 mutant mice generated using CRISPR/Cas9.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by impaired social interaction and communication, and repetitive or restricted interest and behaviors. However, the specific pathogenesis of ASD is still unclear. It has been widely accepted that genetic and environmental risk factors are associated with the pathogenesis of ASD. Paired box2 (Pax2) gene encodes a transcription factor that plays an important role in the development of the central nervous system of humans and mice. In this study, we constructed Pax2 heterozygous gene knockout (Pax2+/-) mice using CRISPR/Cas9 technology and performed several autistic-like behavioral assays, including self-grooming test, sociability approach, the elevated plus maze test and Y maze test. Results showed increased repetitive self-grooming and possible abnormal anxiety-like behavior occur in Pax2+/- mice. Furthermore, no changes were observed in the abilities of sociability and working memory in Pax2+/- mice compared to wild-type C57BL/6 J mice. Finally, we speculated that possible mechanism of abnormal autistic-like behaviors due to the deletion of Pax2 gene.

Integrated analysis of miRNA and mRNA expression profiles in the brains of BTBR mice.

The BTBR T+  Itpr3tf (BTBR) mouse has developmental disorders in brain and many aberrant neuroanatomical structures and brain dysfunction. However, identification of the pathological mechanisms underlying abnormal brain development in the brains of BTBR mice is still lacking. Increasingly evidence showed that epigenetics plays an important role in the processes of brain development. In this study, we analyzed microRNA (miRNA) and mRNA expression profiles in the cortical brain tissue from BTBR mice, using RNA sequencing. As compared to C57BL/6J (B6) mice, 1,271 differentially expressed genes (DEGs) and 36 known differentially expressed miRNAs (DEMs) were found in the brain from BTBR mice. The functional annotation and categories of DEGs and DEMs were analyzed. Integration analysis identified 103 known miRNA-mRNA interaction pairs. We further verified selected several genes and miRNAs which may be associated with brain development using quantitative RT-PCR (qRT-PCR). Finally, we speculate that reduced myelin-associated oligodendrocytic basic protein and transmembrane proteins 260 may be linked with abnormal brain development in BTBR mice.

Elevated lysine crotonylation and succinylation in the brains of BTBR mice.

The BTBR T + Itpr3tf/J (BTBR) mouse has developmental disorders in the central nervous system and many aberrant neuroanatomical structures. However, identification of the pathological mechanisms underlying these abnormal neuroanatomical structures in the brains of BTBR mice is still lacking. Posttranslational modifications (PTMs) are known to be involved in the regulation of diverse cellular processes, and evidence shows that some types of PTMs are associated with the development of the central nervous system. In this study, we detected four novel PTMs in the cerebral cortex of BTBR mice as compared to C57BL/6 J (B6) mice using western blotting. Results revealed that lysine crotonylation and succinylation were elevated in the cerebral cortex of BTBR mice compared to levels in B6 mice. We speculate that elevated profiles of lysine crotonylation and succinylation may be involved in mechanisms related to neuroanatomical abnormalities in cerebral cortex of BTBR mice.

Theoretical explanation for the pharmaceutical incompatibility through the cooperativity effect of the drug-drug intermolecular interactions in the phenobarbital∙∙∙paracetamol∙∙∙H2O complex.

In order to reveal the essence of the pharmaceutical incompatibility, the cooperativity effects of the drug-drug intermolecular π∙∙∙π and H∙∙∙O H-bonding interactions involving hydration were evaluated in the phenobarbital∙∙∙paracetamol∙∙∙H2O complex at the M06-2X/6-311++G** and MP2/6-311++G** levels. The thermodynamic cooperativity effects were also investigated by the statistical thermodynamic method. The results show that the π∙∙∙π stacking ternary complexes with the moderate anti-cooperativity effects are dominant in controling the aggregation process of phenobarbital, paracetamol, and H2O, as is confirmed by the atoms-in-molecules (AIM) and reduced density gradient (RDG) analyses. Therefore, it can be inferred that the anti-cooperativity effect plays an important role in forming the pharmaceutical incompatibility, and thus a deduction on the formation process of the pharmaceutical incompatibility between phenobarbital and paracetamol, with the hydration effect, is given. Several valuable models that relate the features of molecular surface electrostatic potentials or their statistical parameters, such as the surface areas, average values ([Formula: see text]), variances ([Formula: see text], [Formula: see text] and [Formula: see text]), and product of [Formula: see text] and electrostatic balance parameter (ν) ([Formula: see text]ν), to the values of the cooperativity effects were predicted. The formation of the pharmaceutical incompatibility is a thermodynamic cooperativity process driven by the enthalpy change. Graphical abstract Anti-cooperativity effect plays an important role in forming the pharmaceutical incompatibility.

Alpha-synuclein gene polymorphism affects risk of dementia in Han Chinese with Parkinson's disease.

BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the SNCA gene encoding alpha-synuclein have been shown to affect the PD phenotype. However, whether such polymorphisms can influence risk of dementia in PD remains unclear. OBJECTIVES: To investigate possible associations between SNCA gene polymorphisms and dementia in patients with PD. MATERIALS AND METHODS: A consecutive series of 291 PD patients with dementia (n = 45, 15.5%) or without it (n = 246, 84.5%) were genotyped at four SNPs in the SNCA gene. As controls, 615 healthy Han Chinese were also genotyped. RESULTS: Three SNPs (rs11931074, rs7684318 and rs356219) were in strong linkage disequilibrium. The GG genotype at rs11931074 significantly reduced risk of PD (p = 0.023), but it significantly increased risk of dementia after PD onset (p = 0.015) based on the recessive genetic model. Logistic regression identified the following risk factors for dementia among patients with PD: age ≥65 years (odds ratio [OR] 2.69, 95% confidence interval [CI] 1.25-5.77, p = 0.011), education ≤6 years (OR 4.66, 95% CI 2.21-9.83, p < 0.001), part III score on the Unified Parkinson's Disease Rating Scale ≥40 (OR 5.01, 95% CI 2.40-10.45, p < 0.001), and GG genotype at rs11931074 (OR 2.81, 95% CI 1.16-6.83, p = 0.022). CONCLUSIONS: PD patients carrying the protective GG genotype at SNCA rs11931074 may be at significantly higher risk of dementia than patients with other genotypes. Our results support the view that SNCA polymorphisms can have opposite effects on preclinical and clinical PD.

Role of Microtubule-Associated Protein in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social interaction and communication, along with repetitive and restrictive patterns of behaviors or interests. Normal brain development is crucial to behavior and cognition in adulthood. Abnormal brain development, such as synaptic and myelin dysfunction, is involved in the pathogenesis of ASD. Microtubules and microtubule-associated proteins (MAPs) are important in regulating the processes of brain development, including neuron production and synaptic formation, as well as myelination. Increasing evidence suggests that the level of MAPs are changed in autistic patients and mouse models of ASD. Here, we discuss the roles of MAPs.

Reduced plasma levels of microtubule-associated STOP/MAP6 protein in autistic patients.

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits and repetitive behaviors with restricted interests. A previous quantitative proteomic profiling study demonstrated that microtubule-associated stable tubule only polypeptide (STOP; also known as MAP6) protein was significant reduced in the cerebral cortex from BTBR mouse model of autism compared to the C57BL/6J mice. In the present study, the result showed that the concentration of STOP/MAP6 protein was significantly reduced in the plasma of autistic subjects than that in healthy controls. Finally, a possible mechanism of STOP/MAP6 protein in the pathogenesis of autism was proposed.

Reduced Glutamate Release in Adult BTBR Mouse Model of Autism Spectrum Disorder.

Autism spectrum disorder (ASD) is a developmental disorder characterized by impairments in social and communication abilities, as well as by restricted and repetitive behaviors. The BTBR T + Itpr3 tf (BTBR) mice have emerged as a well characterized and widely used mouse model of a range of ASD-like phenotype, showing deficiencies in social behaviors and unusual ultrasonic vocalizations as well as increased repetitive self-grooming. However, the inherited neurobiological changes that lead to ASD-like behaviors in these mice are incompletely known and still under active investigation. The aim of this study was to further evaluate the structure and neurotransmitter release of the glutamatergic synapse in BTBR mice. C57BL/6J (B6) mice were used as a control strain because of their high level of sociability. The important results showed that the evoked glutamate release in the cerebral cortex of BTBR mice was significantly lower than in B6 mice. And the level of vesicle docking-related protein Syntaxin-1A was reduced in BTBR mice. However, no significant changes were observed in the number of glutamatergic synapse, level of synaptic proteins, density of dendritic spine and postsynaptic density between BTBR mice and B6 mice. Overall, our results suggest that abnormal vesicular glutamate activity may underlie the ASD relevant pathology in the BTBR mice.

Inhibition of IL-6 trans-signaling in the brain increases sociability in the BTBR mouse model of autism.

Autism is a severe neurodevelopmental disorder with a large population prevalence, characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. The BTBR T(+)Itpr3(tf) (BTBR) mice have emerged as strong candidates to serve as models of a range of autism-relevant behaviors. Increasing evidences suggest that interleukin (IL)-6, one of the most important neuroimmune factors, was involved in the pathophysiology of autism. It is of great importance to further investigate whether therapeutic interventions in autism can be achieved through the manipulation of IL-6. Our previous studies showed that IL-6 elevation in the brain could mediate autistic-like behaviors, possibly through the imbalances of neural circuitry and impairments of synaptic plasticity. In this study, we evaluate whether inhibiting IL-6 signaling in the brain is sufficient to modulate the autism-like behaviors on the BTBR mice. The results showed that chronic infusion of an analog of the endogenous IL-6 trans-signaling blocker sgp130Fc protein increased the sociability in BTBR mice. Furthermore, no change was observed in the number of excitatory synapse, level of synaptic proteins, density of dentitic spine and postsynaptic density in BTBR cortices after inhibiting IL-6 trans-signaling. However, inhibition of IL-6 trans-signaling increased the evoked glutamate release in synaptoneurosomes from the cerebral cortex of BTBR mice. Our findings suggest that inhibition of excessive production of IL-6 may have selective therapeutic efficacy in treating abnormal social behaviors in autism.

Abnormal glutamate release in aged BTBR mouse model of autism.

Autism is a neurodevelopmental disorder characterized by abnormal reciprocal social interactions, communication deficits, and repetitive behaviors with restricted interests. Most of the available research on autism is focused on children and young adults and little is known about the pathological alternation of autism in older adults. In order to investigate the neurobiological alternation of autism in old age stage, we compared the morphology and synaptic function of excitatory synapses between the BTBR mice with low level sociability and B6 mice with high level sociability. The results revealed that the number of excitatory synapse colocalized with pre- and post-synaptic marker was not different between aged BTBR and B6 mice. The aged BTBR mice had a normal structure of dendritic spine and the expression of Shank3 protein in the brain as well as that in B6 mice. The baseline and KCl-evoked glutamate release from the cortical synaptoneurosome in aged BTBR mice was lower than that in aged B6 mice. Overall, the data indicate that there is a link between disturbances of the glutamate transmission and autism. These findings provide new evidences for the hypothesis of excitation/inhibition imbalance in autism. Further work is required to determine the cause of this putative abnormality.

The apoptotic perspective of autism.

Autism is a severe neurodevelopmental disorder characterized by impairments in social interaction, deficits in verbal and non-verbal communication, and repetitive behavior and restricted interests. The normal brain development during fetal brain development and the first year of life is critical to the behaviors and cognitions in adulthood. Programmed cell death (apoptosis) is an important mechanism that determines the size and shape of the brain and regulates the proper wiring of developing neuronal networks. Pathological activation of apoptotic death pathways under pathological conditions may lead to neuroanatomic abnormalities and possibly to developmental disabilities. It has been demonstrated a possible association between neural cell death and autism. Here, the abnormal apoptosis found in autism from postmortem and animal studies was reviewed and the possible mechanism was discussed.

Up-regulation of Ras/Raf/ERK1/2 signaling impairs cultured neuronal cell migration, neurogenesis, synapse formation, and dendritic spine development.

The Ras/Raf/ERK1/2 signaling pathway controls many cellular responses such as cell proliferation, migration, differentiation, and death. In the nervous system, emerging evidence also points to a death-promoting role for ERK1/2 in both in vitro and in vivo models of neuronal death. Recent studies have suggested that abnormal apoptosis in the central nervous system may be involved in the pathogenesis of autism. Two studies reported that both a microdeletion and microduplication on chromosome 16, which includes the MAPK3 gene that encodes ERK1, are associated with autism. In addition, our recent work showed that Ras/Raf/ERK1/2 signaling activities were significantly up-regulated in the frontal cortex of autistic individuals and in the BTBR murine model of autism. To further investigate how Ras/Raf/ERK1/2 up-regulation may lead to the development of autism, we developed a cellular model of Raf/ERK up-regulation by over-expressing c-Raf in cultured cortical neurons (CNs) and cerebellar granule cells (CGCs). We found that Raf/ERK up-regulation stimulates the migration of both CNs and CGCs, and impairs the formation of excitatory synapses in CNs. In addition, we found that Raf/ERK up-regulation inhibits the development of mature dendritic spines in CNs. Investigating the possible mechanisms through which Raf/ERK up-regulation affects excitatory synapse formation and dendritic spine development, we discovered that Raf/ERK up-regulation suppresses the development and maturation of CNs. Together, these results suggest that the up-regulation of the Raf/ERK signaling pathway may contribute to the pathogenesis of autism through both its impairment of cortical neuron development and causing neural circuit imbalances.

Alteration of brain volume in IL-6 overexpressing mice related to autism.

Abnormal neuroimmune responses have been reported to be associated with autism and could be appropriate targets for pharmacologic intervention. Our previous studies showed that neuroimmune factor, interleukin (IL)-6, was significantly elevated in the fontal cortex and cerebellum of autistic subjects. The IL-6 overexpressing mice displayed several autism-like features as well as an abnormal dendritic spine morphology and synaptic function. The purpose of this study was to examine the volumetric differences in the brain of IL-6 overexpressing mice and compare with corresponding control mice using magnetic resonance imaging. Here we show that IL-6 overexpressing mice display an increase in the total brain volume. In addition, the lateral ventricle is also enlarged in the IL-6 overexpressing mice. The brain structures surrounding the lateral ventricle were squeezed and deformed from the normal location. These results indicate that IL-6 elevation in the brain could mediate neuroanatomical abnormalities. Taking together with our previous findings, a mechanism by which IL-6 may be involved in the pathogenesis of autism is proposed.

The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.