The secreted protein Amuc_1409 from Akkermansia muciniphila improves gut health through intestinal stem cell regulation.

Akkermansia muciniphila has received great attention because of its beneficial roles in gut health by regulating gut immunity, promoting intestinal epithelial development, and improving barrier integrity. However, A. muciniphila-derived functional molecules regulating gut health are not well understood. Microbiome-secreted proteins act as key arbitrators of host-microbiome crosstalk through interactions with host cells in the gut and are important for understanding host-microbiome relationships. Herein, we report the biological function of Amuc_1409, a previously uncharacterised A. muciniphila-secreted protein. Amuc_1409 increased intestinal stem cell (ISC) proliferation and regeneration in ex vivo intestinal organoids and in vivo models of radiation- or chemotherapeutic drug-induced intestinal injury and natural aging with male mice. Mechanistically, Amuc_1409 promoted E-cadherin/ß-catenin complex dissociation via interaction with E-cadherin, resulting in the activation of Wnt/ß-catenin signaling. Our results demonstrate that Amuc_1409 plays a crucial role in intestinal homeostasis by regulating ISC activity in an E-cadherin-dependent manner and is a promising biomolecule for improving and maintaining gut health.

Angiotensin-converting enzyme inhibition prevents l-dopa-induced dyskinesia in a 6-ohda-induced mouse model of Parkinson's disease.

Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin-angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.

Agathobaculum butyriciproducens improves ageing-associated cognitive impairment in mice.

AIMS: The gut microbiota is increasingly recognised as a pivotal regulator of immune system homeostasis and brain health. Recent research has implicated the gut microbiota in age-related cognitive impairment and dementia. Agathobaculum butyriciproducens SR79 T (SR79), which was identified in the human gut, has been reported to be beneficial in addressing cognitive deficits and pathophysiologies in a mouse model of Alzheimer's disease. However, it remains unknown whether SR79 affects age-dependent cognitive impairment. MAIN METHOD: To explore the effects of SR79 on cognitive function during ageing, we administered SR79 to aged mice. Ageing-associated behavioural alterations were examined using the open field test (OFT), tail suspension test (TST), novel object recognition test (NORT), Y-maze alternation test (Y-maze), and Morris water maze test (MWM). We investigated the mechanisms of action in the gut and brain using molecular and histological analyses. KEY FINDINGS: Administration of SR79 improved age-related cognitive impairment without altering general locomotor activity or depressive behaviour in aged mice. Furthermore, SR79 increased mature dendritic spines in the pyramidal cells of layer III and phosphorylation of CaMKIIα in the cortex of aged mice. Age-related activation of astrocytes in the cortex of layers III-V of the aged brain was reduced following SR79 administration. Additionally, SR79 markedly increased IL-10 production and Foxp3 and Muc2 mRNA expression in the colons of aged mice. SIGNIFICANCE: These findings suggest that treatment with SR79 may be a beneficial microbial-based approach for enhancing cognitive function during ageing.

Mucosal TLR5 activation controls healthspan and longevity.

Addressing age-related immunological defects through therapeutic interventions is essential for healthy aging, as the immune system plays a crucial role in controlling infections, malignancies, and in supporting tissue homeostasis and repair. In our study, we show that stimulating toll-like receptor 5 (TLR5) via mucosal delivery of a flagellin-containing fusion protein effectively extends the lifespan and enhances the healthspan of mice of both sexes. This enhancement in healthspan is evidenced by diminished hair loss and ocular lens opacity, increased bone mineral density, improved stem cell activity, delayed thymic involution, heightened cognitive capacity, and the prevention of pulmonary lung fibrosis. Additionally, this fusion protein boosts intestinal mucosal integrity by augmenting the surface expression of TLR5 in a certain subset of dendritic cells and increasing interleukin-22 (IL-22) secretion. In this work, we present observations that underscore the benefits of TLR5-dependent stimulation in the mucosal compartment, suggesting a viable strategy for enhancing longevity and healthspan.

Comparison study of mouse brain tissue by using ToF-SIMS within static limits and hybrid SIMS beyond static limits (dynamic mode).

In the study of degenerative brain diseases, changes in lipids, the main component of neurons, are particularly important because they are used as indicators of pathological changes. One method for the sensitive measurement of biomolecules, especially lipids, is time-of-flight secondary ion mass spectrometry (ToF-SIMS) using pulsed argon cluster ions. In this study, biomolecules including various lipids present in normal mouse brain tissue were measured using ToF-SIMS equipped with pulsed argon cluster primary ions. Based on the ToF-SIMS measurement results, hybrid SIMS (OrbiSIMS), which is a ToF-SIMS system with the addition of an orbitrap mass analyzer, was used to directly identify the biomolecules by the region in the real tissue samples. For this, the results of ToF-SIMS, which measured the tissue samples from a single mouse brain within static limits, were compared with those from OrbiSIMS measured beyond the static limits in terms of the differences in molecular profiling. From this analysis, two types of positive and negative ions were selected for identification, with the OrbiSIMS MS/MS results indicating that the positive ions were glycerophosphocholine and the negative ions were glycerophosphoinositol and sulfatide, a sphingolipid. Then, to confirm the identification of the molecular candidates, lipids were extracted from mirror image tissue samples, and LC-MS/MS also using an orbitrap mass analyzer was performed. As a result, the direct identification of molecular candidate groups distributed in particular regions of the tissue samples via OrbiSIMS was found to be consistent with the identification results by LC-MS/MS for extracted samples.

Agathobaculum butyriciproducens Shows Neuroprotective Effects in a 6-OHDA-Induced Mouse Model of Parkinson's Disease.

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disease and is characterized by dopaminergic neuronal death in the midbrain. Recently, the association between alterations in PD pathology and the gut microbiota has been explored. Microbiota-targeted interventions have been suggested as a novel therapeutic approach for PD. Agathobaculum butyriciproducens SR79T (SR79) is an anaerobic bacterium. Previously, we showed that SR79 treatment induced cognitive improvement and reduced Alzheimer's disease pathologies in a mouse model. In this study, we hypothesized that SR79 treatment may have beneficial effects on PD pathology. To investigate the therapeutic effects of SR79 on PD, 6-hydroxydopamine (6-OHDA)-induced mouse models were used. D-Amphetamine sulfate (d-AMPH)-induced behavioral rotations and dopaminergic cell death were analyzed in unilateral 6-OHDA-lesioned mice. Treatment with SR79 significantly decreased ipsilateral rotations induced by d-AMPH. Moreover, SR79 treatment markedly activated the AKT/GSK3ß signaling pathway in the striatum. In addition, SR79 treatment affected the Nrf2/ARE signaling pathway and its downstream target genes in the striatum of 6-OHDA-lesioned mice. Our findings suggest a protective role of SR79 in 6-OHDA-induced toxicity by regulating the AKT/Nrf2/ARE signaling pathway and astrocyte activation. Thus, SR79 may be a potential microbe-based intervention and therapeutic strategy for PD.

Humulus japonicus attenuates LPS-and scopolamine-induced cognitive impairment in mice.

BACKGROUND: Neuroinflammation plays an important role in cognitive decline and memory impairment in neurodegenerative disorders. Previously, we demonstrated that Humulus japonicus (HJ) has anti-inflammatory effects in rodent models of Alzheimer's disease and Parkinson's disease. The present study aimed to examine the protective potential of HJ extracts against lipopolysaccharide (LPS)-induced cognitive impairment and scopolamine-induced amnesia in mouse models. Cognitive improvement of mice was investigated by novel object recognition test. For analyzing effects on neuroinflammation, immunohistochemistry and quantitative real-time polymerase chain reaction (qRT-PCR) assays were performed. RESULTS: We found that the oral administration of HJ significantly improved cognitive dysfunction induced by LPS in a novel object recognition test. The LPS-induced activation of microglia was notably decreased by HJ treatment in the cortex and hippocampus. HJ administration with LPS also significantly increased the mRNA expression of interleukin (IL)-10 and decreased the mRNA expression of IL-12 in the parietal cortex of mice. The increased expression of LPS-induced complement C1q B chain (C1bq) and triggering receptor expressed on myeloid cells 2 (Trem2) genes was significantly suppressed by HJ treatment. In addition, HJ administration significantly improved novel object recognition in a scopolamine-induced amnesia mouse model. CONCLUSIONS: These findings revealed that HJ has a beneficial effect on cognitive impairment and neuroinflammation induced by systemic inflammation and on amnesia induced by scopolamine in mice.

Simultaneous Multiplexed Imaging of Biomolecules in Transgenic Mouse Brain Tissues Using Mass Spectrometry Imaging: A Multi-omic Approach.

The importance of multi-omic-based approaches to better understand diverse pathological mechanisms including neurodegenerative diseases has emerged. Spatial information can be of great help in understanding how biomolecules interact pathologically and in elucidating target biomarkers for developing therapeutics. While various analytical methods have been attempted for imaging-based biomolecule analysis, a multi-omic approach to imaging remains challenging due to the different characteristics of biomolecules. Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is a powerful tool due to its sensitivity, chemical specificity, and high spatial resolution in visualizing chemical information in cells and tissues. In this paper, we suggest a new strategy to simultaneously obtain the spatial information of various kinds of biomolecules that includes both labeled and label-free approaches using ToF-SIMS. The enzyme-assisted labeling strategy for the targets of interest enables the sensitive and specific imaging of large molecules such as peptides, proteins, and mRNA, a task that has been, to date, difficult for any MS analysis. Together with the strength of the analytical performance of ToF-SIMS in the label-free tissue imaging of small biomolecules, the proposed strategy allows one to simultaneously obtain integrated information of spatial distribution of metabolites, lipids, peptides, proteins, and mRNA at a high resolution in a single measurement. As part of the suggested strategy, we present a sample preparation method suitable for MS imaging. Because a comprehensive method to examine the spatial distribution of multiple biomolecules in tissues has remained elusive, our strategy can be a useful tool to support the understanding of the interactions of biomolecules in tissues as well as pathological mechanisms.

Comprehensive 16S rRNA and metagenomic data from the gut microbiome of aging and rejuvenation mouse models.

The gut microbiota is associated with the health and longevity of the host. A few methods, such as fecal microbiota transplantation and oral administration of probiotics, have been applied to alter the gut microbiome and promote healthy aging. The changes in host microbiomes still remain poorly understood. Here, we characterized both the changes in gut microbial communities and their functional potential derived from colon samples in mouse models during aging. We achieved this through four procedures including co-housing, serum injection, parabiosis, and oral administration of Akkermansia muciniphila as probiotics using bacterial 16 S rRNA sequencing and shotgun metagenomic sequencing. The dataset comprised 16 S rRNA sequencing (36,249,200 paired-end reads, 107 sequencing data) and metagenomic sequencing data (307,194,369 paired-end reads, 109 sequencing data), characterizing the taxonomy of bacterial communities and their functional potential during aging and rejuvenation. The generated data expand the resources of the gut microbiome related to aging and rejuvenation and provide a useful dataset for research on developing therapeutic strategies to achieve healthy active aging.

Behavioral Engagement With Playable Objects Resolves Stress-Induced Adaptive Changes by Reshaping the Reward System.

BACKGROUND: The reward system regulates motivated behavior, and repeated practice of specific motivated behavior might conversely modify the reward system. However, the detailed mechanisms by which they reciprocally regulate each other are not clearly understood. METHODS: Mice subjected to chronic restraint stress show long-lasting depressive-like behavior, which is rescued by continual engagement with playable objects. A series of molecular, pharmacological, genetic, and behavioral analyses, combined with microarray, liquid chromatography, and chemogenetic tools, are used to investigate the neural mechanisms of antidepressive effects of playable objects. RESULTS: Here, we show that repeated restraint induces dopamine surges into the nucleus accumbens-lateral shell (NAc-lSh), which cause upregulation of the neuropeptide PACAP in the NAc-lSh. As repeated stress is continued, the dopamine surge by stressors is adaptively suppressed without restoring PACAP upregulation, and the resulting enhanced PACAP inputs from NAc-lSh neurons to the ventral pallidum facilitate depressive-like behaviors. Continual engagement with playable objects in mice subjected to chronic stress remediates reduced dopamine response to new stressors, enhanced PACAP upregulation, and depressive-like behaviors. Overactivation of dopamine D1 receptors over the action of D2 receptors in the NAc-lSh promotes depressive-like behaviors. Conversely, inhibition of D1 receptors or PACAP upregulation in the NAc-lSh confers resilience to chronic stress-induced depressive-like behaviors. Histochemical and chemogenetic analyses reveal that engagement with playable objects produces antidepressive effects by reshaping the ventral tegmental area-to-NAc-lSh and NAc-lSh-to-ventral pallidum circuits. CONCLUSIONS: These results suggest that behavioral engagement with playable objects remediates depressive-like behaviors by resolving stress-induced maladaptive changes in the reward system.

Maternal exposure to polystyrene nanoplastics causes brain abnormalities in progeny.

As global plastic production continues to grow, microplastics released from a massive quantity of plastic wastes have become a critical environmental concern. These microplastic particles are found in a wide range of living organisms in a diverse array of ecosystems. In this study, we investigated the biological effects of polystyrene nanoplastic (PSNP) on development of the central nervous system using cultured neural stem cells (NSCs) and mice exposed to PSNP during developmental stages. Our study demonstrates that maternal administration of PSNP during gestation and lactating periods altered the functioning of NSCs, neural cell compositions, and brain histology in progeny. Similarly, PSNP-induced molecular and functional defects were also observed in cultured NSCs in vitro. Finally, we show that the abnormal brain development caused by exposure to high concentrations of PSNP results in neurophysiological and cognitive deficits in a gender-specific manner. Our data demonstrate the possibility that exposure to high amounts of PSNP may increase the risk of neurodevelopmental defects.

Ageing and rejuvenation models reveal changes in key microbial communities associated with healthy ageing.

BACKGROUND: The gut microbiota is associated with diverse age-related disorders. Several rejuvenation methods, such as probiotic administration and faecal microbiota transplantation, have been applied to alter the gut microbiome and promote healthy ageing. Nevertheless, prolongation of the health span of aged mice by remodelling the gut microbiome remains challenging. RESULTS: Here, we report the changes in gut microbial communities and their functions in mouse models during ageing and three rejuvenation procedures including co-housing, serum-injection and parabiosis. Our results showed that the compositional structure and gene abundance of the intestinal microbiota changed dynamically during the ageing process. Through the three rejuvenation procedures, we observed that the microbial community and intestinal immunity of aged mice were comparable to those of young mice. The results of metagenomic data analysis underscore the importance of the high abundance of Akkermansia and the butyrate biosynthesis pathway in the rejuvenated mouse group. Furthermore, oral administration of Akkermansia sufficiently ameliorated the senescence-related phenotype in the intestinal systems in aged mice and extended the health span, as evidenced by the frailty index and restoration of muscle atrophy. CONCLUSIONS: In conclusion, the changes in key microbial communities and their functions during ageing and three rejuvenation procedures, and the increase in the healthy lifespan of aged mice by oral administration of Akkermansia. Our results provide a rationale for developing therapeutic strategies to achieve healthy active ageing. Video abstract.

Analyte-Induced Desert Rose-like Ag Nanostructures for Surface-Enhanced Raman Scattering-Based Biomolecule Detection and Imaging.

Biomolecule detection based on surface-enhanced Raman scattering (SERS) for application to biosensors and bio-imaging requires the fabrication of SERS nanoprobes that can generate strong Raman signals as well as surface modifications for analyte-specific recognition and binding. Such requirements lead to disadvantages in terms of reproducibility and practicality, and thus, it has been difficult to apply biomolecule detection utilizing the advantages of the SERS phenomenon to actual clinically relevant analysis. To achieve reproducible and practical SERS signal generation in a biomolecule-specific manner without requiring the synthesis of nanostructures and their related surface modification to introduce molecules for specific recognition, we developed a new type of SERS probe formed by enzyme reactions in the presence of Raman reporters. By forming unique plasmonic structures, our method achieves the detection of biomolecules on chips with uniform and stable signals over long periods. To test the proposed approach, we applied it to a SERS-based immunohistochemistry assay and found successful multiplexed protein detection in brain tissue from transgenic mice.

Nanoplasmonic immunosensor for the detection of SCG2, a candidate serum biomarker for the early diagnosis of neurodevelopmental disorder.

The neural circuits of the infant brain are rapidly established near 6 months of age, but neurodevelopmental disorders can be diagnosed only at the age of 2-3 years using existing diagnostic methods. Early diagnosis is very important to alleviate life-long disability in patients through appropriate early intervention, and it is imperative to develop new diagnostic methods for early detection of neurodevelopmental disorders. We examined the serum level of secretogranin II (SCG2) in pediatric patients to evaluate its potential role as a biomarker for neurodevelopmental disorders. A plasmonic immunosensor performing an enzyme-linked immunosorbent assay (ELISA) on a gold nanodot array was developed to detect SCG2 in small volumes of serum. This nanoplasmonic immunosensor combined with tyramide signal amplification was highly sensitive to detect SCG2 in only 5 µL serum samples. The analysis using the nanoplasmonic immunosensor revealed higher serum SCG2 levels in pediatric patients with developmental delay than in the control group. Overexpression or knockdown of SCG2 in hippocampal neurons significantly attenuated dendritic arborization and synaptic formation. These results suggest that dysregulated SCG2 expression impairs neural development. In conclusion, we developed a highly sensitive nanoplasmonic immunosensor to detect serum SCG2, a candidate biomarker for the early diagnosis of neurodevelopmental disorders.

Humulus japonicus rescues autistic­like behaviours in the BTBR T+ Itpr3tf/J mouse model of autism.

Humulus japonicus (HJ) is a traditional herbal medicine that exhibits anti­inflammatory, antimicrobial and anti­tumor effects that is used for the treatment of hypertension, pulmonary disease and leprosy. Recently, it has also been reported that HJ demonstrates neuroprotective properties in animal models of neurodegenerative diseases. The current study hypothesised that the administration of HJ would exhibit therapeutic effects in autism spectrum disorder (ASD), a neurodevelopmental disorder with lifelong consequences. The BTBR T+ Itpr3tf/J mouse model of ASD was used to investigate the anti­autistic like behavioural effects of HJ. Chronic oral administration of the ethanolic extract of HJ significantly increased social interaction, attenuated repetitive grooming behaviour and improved novel­object recognition in BTBR mice. Anti­inflammatory effects of HJ in the brain were analysed using immunohistochemistry and reverse­transcription quantitative PCR analysis. Microglia activation was markedly decreased in the striatum and hippocampus, and pro­inflammatory cytokines, including C­C Motif Chemokine Ligand 2, interleukin (IL)­1ß and IL­6, were significantly reduced in the hippocampus following HJ treatment. Moreover, HJ treatment normalised the phosphorylation levels of: N­methyl­D­aspartate receptor subtype 2B and calcium/calmodulin­dependent protein kinase type II subunit α in the hippocampus of BTBR mice. The results of the present study demonstrated that the administration of HJ may have beneficial potential for ameliorating behavioural deficits and neuroinflammation in ASD.

Sodium phenylbutyrate reduces repetitive self-grooming behavior and rescues social and cognitive deficits in mouse models of autism.

Autism spectrum disorder (ASD) is a neurodevelopment disorder characterized by deficits in social interaction and restrictive, repetitive, and stereotypical patterns of behavior. However, there is no pharmacological drug that is currently used to target these core ASD symptoms. Sodium phenylbutyrate (NaPB) is a well-known long-term treatment of urea cycle disorders in children. In this study, we assessed the therapeutic effects of NaPB, which is a chemical chaperone as well as histone deacetylase inhibitor on a BTBR T + Itpr3tf/J (BTBR) mice model of ASD. We found that acute and chronic treatment of NaPB remarkably improved, not only core ASD symptoms, including repetitive behaviors and sociability deficit, but also cognitive impairment in the BTBR mice. NaPB substantially induced histone acetylation in the brain of the BTBR mice. Intriguingly, the therapeutic effects of NaPB on autistic-like behaviors, such as repetitive behaviors, impaired sociability, and cognitive deficit also showed in the valproic acid (VPA)-induced mouse model of autism. In addition, pentylenetetrazole (PTZ)-induced seizure was significantly attenuated by NaPB treatment in C57BL/6J and BTBR mice. These findings suggest that NaPB may provide a novel therapeutic approach for the treatment of patients with ASD.

Human gut microbiota Agathobaculum butyriciproducens improves cognitive impairment in LPS-induced and APP/PS1 mouse models of Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease, and is characterized by the accumulation and presence of amyloid plaques (Aß), tangles, dementia, and cognitive impairment. Currently, there is no known cure for AD; however, recently, the association between alteration of the gut microbiota and AD pathology has been explored to find novel therapeutic approaches. Microbiota-targeted intervention has been suggested as an attractive therapeutic approach for AD. Agathobaculum butyriciproducens (SR79) is a strict anaerobic and butyric acid-producing bacteria. We hypothesized that administration of SR79 might have a beneficial effect on cognitive deficits and AD pathologies. To determine the therapeutic effects of SR79 on AD pathologies, APP/PS1 transgenic and lipopolysaccharide -induced cognitive impairment mouse models were used. In the lipopolysaccharide -induced cognitive deficit model, the administration of SR79 improved cognitive function and decreased microglia activation. In addition, the administration of SR79 to APP/PS1 mice significantly improved novel object recognition and percent alteration results in novel object recognition and Y-maze alteration tests. Furthermore, Aß plaque deposition and microglial activation were markedly reduced in the parietal cortex and hippocampus after SR79 treatment in APP/PS1 mice. SR79 treatment significantly decreased gene expression levels of IL-1ß and C1QB and increased the gene expression levels of IGF-1 and thereby the downstream signaling pathway in the cortex of APP/PS1 mice. In conclusion, SR79 administration improved cognitive function and AD pathologies through the regulation of neuroinflammation and IGF-1 signaling in an animal model.

ß­Lapachone ameliorates L­DOPA­induced dyskinesia in a 6­OHDA­induced mouse model of Parkinson's disease.

The dopamine precursor 3,4­dihydroxyphenyl­ l­alanine (L­DOPA) is the most widely used symptomatic treatment for Parkinson's disease (PD); however, its prolonged use is associated with L­DOPA­induced dyskinesia in more than half of patients after 10 years of treatment. The present study investigated whether co­treatment with ß­Lapachone, a natural compound, and L­DOPA has protective effects in a 6­hydroxydopamine (6­OHDA)­induced mouse model of PD. Unilateral 6­OHDA­lesioned mice were treated with vehicle or ß­Lapachone (10 mg/kg/day) and L­DOPA for 11 days. Abnormal involuntary movements (AIMs) were scored on days 5 and 10. ß­Lapachone (10 mg/kg) co­treatment with L­DOPA decreased the AIMs score on both days 5 and 10. ß­Lapachone was demonstrated to have a beneficial effect on the axial and limb AIMs scores on day 10. There was no significant suppression in dopamine D1 receptor­related and ERK1/2 signaling in the DA­denervated striatum by ß­Lapachone­cotreatment with L­DOPA. Notably, ß­Lapachone­cotreatment with L­DOPA increased phosphorylation at the Ser9 site of glycogen synthase kinase 3ß (GSK­3ß), indicating suppression of GSK­3ß activity in both the unlesioned and 6­OHDA­lesioned striata. In addition, astrocyte activation was markedly suppressed by ß­Lapachone­cotreatment with L­DOPA in the striatum and substantia nigra of the unilateral 6­OHDA model. These findings suggest that ß­Lapachone cotreatment with L­DOPA therapy may have therapeutic potential for the suppression or management of the development of L­DOPA­induced dyskinesia in patients with PD.

Depression-like behaviors induced by defective PTPRT activity through dysregulated synaptic functions and neurogenesis.

PTPRT has been known to regulate synaptic formation and dendritic arborization of hippocampal neurons. PTPRT-/- null and PTPRT-D401A mutant mice displayed enhanced depression-like behaviors compared with wild-type mice. Transient knockdown of PTPRT in the dentate gyrus enhanced the depression-like behaviors of wild-type mice, whereas rescued expression of PTPRT ameliorated the behaviors of PTPRT-null mice. Chronic stress exposure reduced expression of PTPRT in the hippocampus of mice. In PTPRT-deficient mice the expression of GluR2 (also known as GRIA2) was attenuated as a consequence of dysregulated tyrosine phosphorylation, and the long-term potentiation at perforant-dentate gyrus synapses was augmented. The inhibitory synaptic transmission of the dentate gyrus and hippocampal GABA concentration were reduced in PTPRT-deficient mice. In addition, the hippocampal expression of GABA transporter GAT3 (also known as SLC6A11) was decreased, and its tyrosine phosphorylation was increased in PTPRT-deficient mice. PTPRT-deficient mice displayed reduced numbers and neurite length of newborn granule cells in the dentate gyrus and had attenuated neurogenic ability of embryonic hippocampal neural stem cells. In conclusion, our findings show that the physiological roles of PTPRT in hippocampal neurogenesis, as well as synaptic functions, are involved in the pathogenesis of depressive disorder.