MiR-501-3p functions as a tumor suppressor in non-small cell lung cancer by downregulating RAP1A.

MicroRNA-501-3p (miR-501-3p) has been reported to play tumor-suppressive roles in different cancers; however, its expression pattern and biological function in non-small cell lung cancer (NSCLC) remain unknown. In this study, we noted downregulation of miR-501-3p in NSCLC tissues and cell lines. Functional assays showed that overexpression of miR-501-3p suppressed NSCLC cell proliferation, clonogenicity, migration, and invasion. Moreover, miR-501-3p overexpression attenuated in vivo tumor growth in a nude mouse model. In terms of the mechanism, RAP1A was identified as a novel target of miR-501-3p. Overexpression of RAP1A strongly attenuated the inhibitory effects of miR-501-3p on the capacity of NSCLC cells for proliferation and motility. In the clinical samples of NSCLC, miR-501-3p levels negatively correlated with RAP1A expression, which was upregulated in NSCLC. Collectively, these results indicate that miR-501-3p acts as a tumor suppressor in NSCLC by directly targeting RAP1A mRNA and may serve as a theranostic biomarker for patients with NSCLC.

Hydroxysafflor Yellow A Confers Neuroprotection from Focal Cerebral Ischemia by Modulating the Crosstalk Between JAK2/STAT3 and SOCS3 Signaling Pathways.

Natural bioactive compounds have increasingly proved to be promising in evidence- or target-directed treatment or modification of a spectrum of diseases including cerebral ischemic stroke. Hydroxysafflor yellow A (HSYA), a major active component of the safflower plant, has drawn more interests in recent year for its multiple pharmacological actions in the treatment of cerebrovascular and cardiovascular diseases. Although the Janus kinase signaling, such as JAK2/STAT3 pathway, has been implicated in the modulation of the disease, the inhibition or activation of the pathway that contributed to the neuronal prevention from ischemic damages remains controversial. In this study, a series of experiments were performed to examine the dose- and therapeutic time window-related pharmacological efficacies of HSYA with emphasis on the HSYA-modulated interaction of JAK2/STAT3 and SOCS3 signaling in the MCAO rats. We found that HSYA treatment significantly rescued the neurological and functional deficits in a dose-dependent manner in the MCAO rats within 3 h after ischemia. HSYA treatment with a dosage of 8 mg/kg or higher markedly downregulated the expression of the JAK2-mediated signaling that was activated in response to ischemic insult, while it also promoted the expression of SOCS3 coordinately. In the subsequent experiments with the use of the JAK2 inhibitor WP1066, we found that the treatment of WP1066 alone or combination of WP1066/HSYA all exhibited inhibitory effects on JAK2-mediated signaling, while there was no influence on the SOCS3 activity of corresponding efficacious data in the MCAO rats, suggesting that excessive activation of JAK2/STAT3 might be necessary for HSYA to provoke SOCS3-negative feedback signaling. Taking together, our study demonstrates that HSYA might modulate the crosstalk between JAK2/STAT3 and SOCS3 signaling pathways that eventually contributed to its therapeutic roles against cerebral ischemic stroke.

Design, synthesis, and structure activity relationship (SAR) studies of novel imidazo[1,2-a] pyridine derivatives as Nek2 inhibitors.

Never in mitosis (NIMA) related kinase 2 (Nek2) is involved in multiple cellular processes such as cell cycle checkpoint regulation, cell division, DNA damage response and cell apoptosis. Nek2 has been reported to be overexpressed in various tumors and correlated with poor prognosis. Herein, a series of imidazo[1,2-a] pyridines Nek2 inhibitors were designed, synthesized, and their biological activities were investigated. Besides, structure activity relationship analysis of these compounds were performed in the MGC-803 cell. The screening results are promising, and compound 28e shows good proliferation inhibitory activity with an IC50 of 38 nM. The results would be helpful to design and develop more effective Nek2 inhibitors for the treatment of gastric cancer.

Rescuing Kv10.2 protein changes cognitive and emotional function in kainic acid-induced status epilepticus rats.

Voltage-gated potassium (Kv) channels are widely expressed in the central and peripheral nervous system and are crucial mediators of neuronal excitability. Importantly, these channels also actively participate in cellular and molecular signaling pathways that regulate the life and death processes of neurons. The current study used a kainic acid (KA)-induced temporal lobe epilepsy model to examine the role of the Kv10.2 gene in status epilepticus (SE). Lentiviral plasmids containing the coding sequence region of the KCNH5 gene (LV-KCNH5) were injected into the CA3 subarea of the right dorsal hippocampus within 24 h in post-SE rats to rescue Kv10.2 protein expression. Open-field and elevated plus maze test results indicated that anxiety-like behavior was ameliorated in the KA + LV-KCNH5 group rats compared with the SE group rats, and working memory was improved in the Y-maze test. However, the spatial reference memory of the LV-KCNH5 group rats did not improve in the Morris water maze test, and no difference was found in the light-dark transition box test. The results of this study indicate that Kv10.2 protein may play an important role in epilepsy, providing new potential therapeutic directions and drug targets for epilepsy treatment.

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting ß-Catenin.

BACKGROUND/AIMS: The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is a basic leucine zipper transcription factor that plays essential roles in tumor progression. Although decreased or absent C/EBPα expression in many cancers suggests a possible role for C/EBPα as a tumor suppressor, the functions of C/EBPα in lung adenocarcinoma remain unclear. METHODS: Here, C/EBPα expression levels in 26 lung adenocarcinoma and para-carcinoma tissue samples were detected by qRT-PCR and immunohistochemistry. Cell transwell assays, wound healing assay and three-dimensional spheroid invasion assay were performed to assess the effects of C/EBPα on migration and invasion in lung adenocarcinoma cells in vitro. Western blotting was applied to analyze the potential mechanisms. RESULTS: C/EBPα was found to be decreased in lung adenocarcinoma tissues compared to para-carcinoma tissues. Overexpression of C/EBPα significantly inhibited the migration and invasion of lung adenocarcinoma cells. In addition, C/EBPα overexpression suppressed the epithelial-mesenchymal transition (EMT) that was characterized by a gain of epithelial and loss of mesenchymal markers. Further study showed that C/EBPα suppressed the transcription of ß-catenin and downregulated the levels of its downstream targets. CONCLUSION: Our data suggest that C/EBPα inhibits lung adenocarcinoma cell invasion and migration by suppressing ß-catenin-mediated EMT in vitro. Thus, C/EBPα may be helpful as a potential target for treatment of lung adenocarcinoma.

Lgr4 protein deficiency induces ataxia-like phenotype in mice and impairs long term depression at cerebellar parallel fiber-Purkinje cell synapses.

Cerebellar dysfunction causes ataxia characterized by loss of balance and coordination. Until now, the molecular and neuronal mechanisms of several types of inherited cerebellar ataxia have not been completely clarified. Here, we report that leucine-rich G protein-coupled receptor 4 (Lgr4/Gpr48) is highly expressed in Purkinje cells (PCs) in the cerebellum. Deficiency of Lgr4 leads to an ataxia-like phenotype in mice. Histologically, no obvious morphological changes were observed in the cerebellum of Lgr4 mutant mice. However, the number of PCs was slightly but significantly reduced in Lgr4(-/-) mice. In addition, in vitro electrophysiological analysis showed an impaired long term depression (LTD) at parallel fiber-PC (PF-PC) synapses in Lgr4(-/-) mice. Consistently, immunostaining experiments showed that the level of phosphorylated cAMP-responsive element-binding protein (Creb) was significantly decreased in Lgr4(-/-) PCs. Furthermore, treatment with forskolin, an adenylyl cyclase agonist, rescued phospho-Creb in PCs and reversed the impairment in PF-PC LTD in Lgr4(-/-) cerebellar slices, indicating that Lgr4 is an upstream regulator of Creb signaling, which is underlying PF-PC LTD. Together, our findings demonstrate for first time an important role for Lgr4 in motor coordination and cerebellar synaptic plasticity and provide a potential therapeutic target for certain types of inherited cerebellar ataxia.

Forebrain NR2B overexpression enhancing fear acquisition and long-term potentiation in the lateral amygdala.

N-methyl-d-aspartic acid (NMDA) receptor-dependent long-term potentiation (LTP) at the thalamus-lateral amygdala (T-LA) synapses is the basis for acquisition of auditory fear memory. However, the role of the NMDA receptor NR2B subunit in synaptic plasticity at T-LA synapses remains speculative. In the present study, using transgenic mice with forebrain-specific overexpression of the NR2B subunit, we have observed that forebrain NR2B overexpression results in enhanced LTP but does not alter long-term depression (LTD) at the T-LA synapses in transgenic mice. To elucidate the cellular mechanisms underlying enhanced LTP at T-LA synapses in these transgenic mice, AMPA and NMDA receptor-mediated postsynaptic currents have been measured. The data show a marked increasing in the amplitude and decay time of NMDA receptor-mediated currents in these transgenic mice. Consistent with enhanced LTP at T-LA synapses, NR2B-transgenic mice exhibit better performance in the acquisition of auditory fear memory than wild-type littermates. Our results demonstrate that up-regulation of NR2B expression facilitates acquisition of auditory cued fear memory and enhances LTP at T-LA synapses.

Alpha7 nicotinic acetylcholine receptor agonist PHA-543613 improves memory deficits in presenilin 1 and presenilin 2 conditional double knockout mice.

Cholinergic system dysfunction has been considered as a critical feature of neurodegenerative progression in Alzheimer's disease (AD). The α7 nicotinic acetylcholine receptors (α7-nAChRs) are widely expressed in the hippocampus cortex and play an important role in memory formation, considered as potential therapeutic agents targets. However, underlying mechanisms have not been fully elucidated. Here, we combine behavioral, molecular biological methods with in vitro slice and in vivo multichannel electrophysiological recording techniques to investigate the molecular, cellular synaptic and neuronal mechanisms of activating α7-nAChR by PHA-543613 (a selective α7-nAChR agonist), which influences the impaired cognitive function using presenilin 1 (PS1) and presenilin 2 (PS2) conditional double knockout (cDKO) mice. Our results demonstrated that PHA-543613 treatment significantly improved the impaired hippocampus-related memory via recovering the reduced the hippocampal synaptic protein levels of α7-nAChR, NMADAR and AMPAR, thereby restoring the impaired post-tetanic potentiation (PTP), long-term potentiation (LTP), activation of molecular signaling pathway for neuronal protection, theta power and strength of theta-gamma phase-amplitude coupling (PAC) at hippocampus in 6-month-old cDKO mice. For the first time, we systematically reveal the mechanisms by which PHA-543613 improves memory deficits at different levels. Therefore, our findings may be significant for the development of therapeutic strategies for AD.

Propofol improves learning and memory in post-traumatic stress disorder (PTSD) mice via recovering hippocampus synaptic plasticity.

AIMS: Propofol, the most commonly used intravenous anesthetic, is known for its protective effect in various human and animal disease models such as post-traumatic stress disease (PTSD). However, it still needs efforts to clarify the effect of propofol on fear memory extinction and the relevant mechanisms. METHODS: Fear memory extinction was examined in PTSD mice model. Thirty-six mice were randomly divided into three groups: a shock + propofol group (sh + Pro), shock + normal saline group (sh + NS), and sham group. The mice were treated with propofol (150 mg/kg) or normal saline (of the same volume) intraperitoneally 30 min after the conditioning. These mice's behavior was analysed with contextual test, sucrose preference test (SPT) and Morris water maze (MWM). Additionally, the synaptic plasticity of the hippocampus was examined by long-term potentiation (LTP) and long-term depression (LTD). KEY FINDINGS: Compared with the sham group, the sh + NS group showed increased freezing time and depressive behavior, meanwhile the sh + Pro group showed minor behavioral changes. What's more, we found that propofol rescued the impaired long-term potentiation (LTP) and long-term depression (LTD) in hippocampus of PTSD mice. All these suggest that propofol can accelerate fear memory extinction and change synaptic plasticity of PTSD mice. SIGNIFICANCE: The study proved that propofol can protect the mice from PTSD by reserving synaptic plasticity and brought a new insight into PTSD treatment indicating that propofol maybe a potential cure for PTSD.

The role of hippocampal CaMKII in resilience to trauma-related psychopathology.

Traumatic stress exposure can form persistent trauma-related memories. However, only a minority of individuals develop post-traumatic stress disorder (PTSD) symptoms upon exposure. We employed a rat model of PTSD, which enables differentiating between exposed-affected and exposed-unaffected individuals. Two weeks after the end of exposure, male rats were tested behaviorally, following an exposure to a trauma reminder, identifying them as trauma 'affected' or 'unaffected.' In light of the established role of hippocampal synaptic plasticity in stress and the essential role of Ca2+/calmodulin-dependent protein kinase II (CaMKII) in hippocampal based synaptic plasticity, we pharmacologically inhibited CaMKII or knocked-down (kd) αCaMKII (in two separate experiments) in the dorsal dentate gyrus of the hippocampus (dDG) following exposure to the same trauma paradigm. Both manipulations brought down the prevalence of 'affected' individuals in the trauma-exposed population. A day after the last behavioral test, long-term potentiation (LTP) was examined in the dDG as a measure of synaptic plasticity. Trauma exposure reduced the ability to induce LTP, whereas, contrary to expectation, αCaMKII-kd reversed this effect. Further examination revealed that reducing αCaMKII expression enables the formation of αCaMKII-independent LTP, which may enable increased resilience in the face of a traumatic experience. The current findings further emphasize the pivotal role dDG has in stress resilience.

Exogenous Aß1-42 monomers improve synaptic and cognitive function in Alzheimer's disease model mice.

Growing evidence has suggested the poor correlation between brain amyloid plaque and Alzheimer's disease (AD). Presenilin1 (PS1) and presenilin2 (PS2) conditional double knockout (cDKO) mice exhibited the reduced 42-amino acid amyloid-ß peptide (Aß1-42) level and AD-like symptoms, indicating a different pathological mechanism from the amyloid cascade hypothesis for AD. Here we found that exogenous synthetic Aß1-42 monomers could improve the impaired memory not only in cDKO mice without Aß1-42 deposition but also in the APP/PS1/Tau triple transgenic 3 × Tg-AD mice with Aß1-42 deposition, which were mediated by α7-nAChR. Our findings demonstrate for the first time that reduced soluble Aß1-42 level is the main cause of cognitive dysfunction in cDKO mice, and support the opinions that low soluble Aß1-42 level due to Aß1-42 deposition may also cause cognitive deficits in 3 × Tg-AD mice. Therefore, "loss-of-function" of Aß1-42 should be avoided when designing therapies aimed at reducing Aß1-42 burden in AD.

Forebrain GluN2A overexpression impairs fear extinction and NMDAR-dependent long-term depression in the lateral amygdala.

N-methyl-d-aspartic acid receptor (NMDAR)-dependent synaptic plasticity at the thalamus-lateral amygdala (T-LA) synapses is related to acquisition and extinction of auditory fear memory. However, the roles of the NMDAR GluN2A subunit in acquisition and extinction of auditory fear memory as well as synaptic plasticity at T-LA synapses remain unclear. Here, using electrophysiologic, molecular biological techniques and behavioral methods, we found that the forebrain specific GluN2A overexpression transgenic (TG) mice exhibited normal acquisition but impaired extinction of auditory fear memory. In addition, in vitro electrophysiological data showed normal basal synaptic transmission and NMDAR-dependent long-term potentiation (LTP) at T-LA synapses, but deficit in NMDAR-dependent long-term depression (LTD) at T-LA synapses in GluN2A TG mice. Consistent with the reduced NMDAR-dependent LTD, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization was also weakened during NMDAR-dependent LTD in GluN2A TG mice. Taken together, our findings for the first time indicate that GluN2A overexpression impairs extinction of auditory fear memory and NMDAR-dependent LTD at T-LA synapses, which further confirms the close relationship between NMDAR-dependent LTD and fear extinction.

αCaMKII in the lateral amygdala mediates PTSD-Like behaviors and NMDAR-Dependent LTD.

Post-traumatic stress disorder (PTSD) is a psychiatric disorder that afflicts many individuals. However, its molecular and cellular mechanisms remain largely unexplored. Here, we found PTSD susceptible mice exhibited significant up-regulation of alpha-Ca2+/calmodulin-dependent kinase II (αCaMKII) in the lateral amygdala (LA). Consistently, increasing αCaMKII in the LA not only caused PTSD-like behaviors such as impaired fear extinction and anxiety-like behaviors, but also attenuated N-methyl-D-aspartate receptor (NMDAR)-dependent long-term depression (LTD) at thalamo-lateral amygdala (T-LA) synapses, and reduced GluA1-Ser845/Ser831 dephosphorylation and a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization. Suppressing the elevated αCaMKII to normal levels completely rescued both PTSD-like behaviors and the impairments in LTD, GluA1-Ser845/Ser831 dephosphorylation, and AMPAR internalization. Intriguingly, deficits in GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization were detected not only after impaired fear extinction, but also after attenuated LTD. Our results suggest that αCaMKII in the LA may be a potential molecular determinant of PTSD. We further demonstrate for the first time that GluA1-Ser845/Ser831 dephosphorylation and AMPAR internalization are molecular links between fear extinction and LTD.

Polysaccharides from Lycium barbarum ameliorate amyloid pathology and cognitive functions in APP/PS1 transgenic mice.

Alzheimer's disease (AD) is the most common degenerative disease of the central nervous system. It is associated with abnormal accumulation of amyloid-ß (Aß) plaques, impaired neurogenesis, and damaged cognitive functions. We have known for a long time that natural compounds and their derivatives have gained increasing attention in AD drug research due to their multiple effects and inherently enormous chemicals. In this study, we will demonstrate that polysaccharides from L. barbarum (LBP1), a traditional natural compound, can reduce Aß level and improve the cognitive functions in APP/PS1 transgenic mouse. LBP1 can enhance neurogenesis as indicated by BrdU/NeuN double labeling. Furthermore, it can restore synaptic dysfunction at hippocampus CA3-CA1 pathway. Additionally, in vitro cell assay indicates that LBP1 may affect Aß processing. In conclusion, our study indicates that LBP1 might be a potential therapeutic agent for the treatment of AD against multiple targets that include synaptic plasticity, Aß pathology and neuropathology.

Human Neural Stem Cells Reinforce Hippocampal Synaptic Network and Rescue Cognitive Deficits in a Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is characterized by memory impairments in its earliest clinical phase. The synaptic loss and dysfunction leading to failures of synaptic networks in AD brain directly cause cognitive deficits of patient. However, it remains unclear whether the synaptic networks in AD brain could be repaired. In this study, we generated functional human induced neural progenitor/stem cells (iNPCs) that had been transplanted into the hippocampus of immunodeficient wild-type and AD mice. The grafted human iNPCs efficiently differentiated into neurons that displayed long-term survival, progressively acquired mature membrane properties, formed graft-host synaptic connections with mouse neurons and functionally integrated into local synaptic circuits, which eventually reinforced and repaired the neural networks of host hippocampus. Consequently, AD mice with human iNPCs exhibited enhanced synaptic plasticity and improved cognitive abilities. Together, our results suggest that restoring synaptic failures by stem cells might provide new directions for the development of novel treatments for human AD.

Inhibition of martentoxin on neuronal BK channel subtype (alpha+beta4): implications for a novel interaction model.

Martentoxin as a 37-residue peptide was capable of blocking large-conductance Ca(2+)-activated K(+) (BK) channels in adrenal medulla chromaffin cells. This study investigated the pharmacological discrimination of martentoxin on BK channel subtypes. The results showed that the iberiotoxin-insensitive neuronal BK channels (alpha+beta4) could be potently blocked by martentoxin (IC(50) = approximately 80 nM). In contrast, the iberiotoxin-sensitive BK channel consisting of only alpha-subunit was less sensitive to martentoxin. Distinctively, martentoxin inhibited neuronal BK channels (alpha+beta4) with a novel interaction mode. Two possible interaction sites of neuronal BK channels (alpha+beta4) might be responsible for the binding with martentoxin: one for trapping and the other located at the pore region for blocking. In addition, the inhibition of martentoxin on neuronal BK channels (alpha+beta4) depended on cytoplasmic Ca(2+) concentration. On the other hand, in vivo experiments from EEG recordings suggested that neuronal BK channels (alpha+beta4) were the primary target of martentoxin. Therefore, this research not only sheds light on a unique ligand for neuronal BK channels (alpha+beta4), but also highlights a novel model approach for the interaction between K(+) channels and specific-ligands.

Down-regulation of Stat3 induces apoptosis of human glioma cell: a potential method to treat brain cancer.

OBJECTIVES: Glioma is the most common brain tumor in central nervous system. Traditional therapies are not effective to cure this disease. Stat3 is a member of the signal transducer and activator of transcription family, and it has the potential to mediate cell survival, growth and differentiation. METHODS: In this study, we testified that Stat3 was constitutively expressed in glioma cell line SHG44 and then investigated the role of a low level of Stat3 expression in glioma cells by constructing an interfering RNA expression plasmid. RESULTS: The results showed that glioma cells underwent morphologic and biochemical changes after the RNAi treatment. DISCUSSION: We hypothesized that a low level of Stat3 expression could induce apoptosis of glioma cell, which further proved that Stat3 played an important role in growth, survival and proliferation of glioma cells. This study provides a new alternative to gene therapy for glioma treatment.

Hydroxysafflor Yellow A (HSYA) Improves Learning and Memory in Cerebral Ischemia Reperfusion-Injured Rats via Recovering Synaptic Plasticity in the Hippocampus.

Hydroxysafflor yellow A (HSYA) is the major active chemical component of the safflower plant flower, which is widely used in Chinese medicine for cerebrovascular and cardiovascular disease treatment. Recent studies have demonstrated that HSYA exerts neuroprotective effect on cerebral ischemia, such as neuronal anti-apoptosis, antioxidant activity and oxygen free radical-scavenging. However, whether and how HSYA has a protective effect on cognitive impairment induced by cerebral ischemia reperfusion remains elusive. In the present study, by using the middle cerebral artery occlusion (MCAO) model, we found that 8 mg/kg and 16 mg/kg HSYA administration by common carotid artery (CCA) injection improved impaired cognitive function in Morris water maze (MWM) and passive avoidance tasks, but not 4 mg/kg HSYA treatment, suggesting that HSYA treatment in a certain concentration can improve cognitive impairment in MCAO rats. Furthermore, we found that 8 mg/kg HSYA treatment rescued the impaired long-term potentiation (LTP) in hippocampus of MCAO rats. Taken together, these results for the first time demonstrate that HSYA has the capacity to protect cognitive function and synaptic plasticity against cerebral ischemia-reperfusion injury, and provide a new insight that HSYA may be a promising alternative for recovery of cognitive dysfunction after brain ischemic injury.

Electroacupuncture restores hippocampal synaptic plasticity via modulation of 5-HT receptors in a rat model of depression.

OBJECTIVE: The study aimed to determine the effect of electroacupuncture (EA) on Wistar Kyoto (WKY) depressive model rats and explore the possible mechanism of EA on hippocampal CA1 region neuronal synaptic plasticity. METHODS: The male WKY rats were randomized to three experimental groups (EA, Sham EA, and Model group, n = 8/group), and Wistar rats as the normal control group (n = 8). EA treatment was administered once daily for 3 weeks at acupuncture points Baihui (GV20) and Yintang (EX-HN3). In the Sham EA group, acupuncture needles were inserted superficially into the acupoints without electrical stimulation. On day 21, the forced swimming test (FST), open field test (OFT) and sucrose preference test (SPT) were conducted. After the behavioral tests, long-term potentiation (LTP) was evoked at Schaffer collateral-CA1 synapses in hippocampal slices in vitro by electrophysiological recording, 5-HTT, 5-HT1A and 5-HT1 B protein levels in the hippocampus CA1 region were examined by using Western blot. RESULT: EA significantly decreased immobility in FST and improved sucrose intake compared with the Sham EA and Model groups. The center time and total move time in OFT were significantly increased in the EA group compared to the Model group. Compared with those of the Sham EA and Model groups, the fEPSP slope of the EA group increased significantly, and the LTP induction was successful. EA significantly decreased 5-HTT protein expression in the hippocampus CA1 region in comparison to the Sham EA and Model groups. Additionally, EA down regulated the 5-HT1A protein expression in the hippocampus CA1 region in comparison to the Sham EA group. CONCLUSION: EA could ameliorate depressive-like behaviors by restoring hippocampus CA1 synaptic plasticity, which might be mainly mediated by regulating 5-HT receptor levels.

Striatal GluN2B involved in motor skill learning and stimulus-response learning.

Although the striatum has a well-documented role in procedural learning and memory, the underlying mechanisms remain poorly understood. GluN2B subunit is abundantly expressed in striatum, however, the function of striatal GluN2B subunit in striatum-related learning is also unclear. In the present study, using transgenic mice with forebrain-specific overexpression of the GluN2B subunit, we observed that up-regulation of GluN2B subunit expression results in enhanced dorsal striatum-related motor skill learning and stimulus-response (S-R) learning as well as cortico-dorsomedial striatal (cortico-DMS) long-term potentiation (LTP). Consistent with the above results, we also found that GluN2B transgenic mice exhibited a remarkable increase in N-methyl-d-aspartic acid receptor (NMDAR) mediated currents in the dorsomedial striatum. In addition, in order to further verify that striatal GluN2B is involved in the dorsal striatum-related cognitive function, lentivirus-mediated short hairpin RNA (shRNA) was used to silence the expression of GluN2B gene in the dorsomedial striatum. As a consequence of down-regulation of dorsomedial striatal GluN2B subunit expression, defective motor skill learning and S-R learning were observed in the GluN2B-shRNA mice. Furthermore, the impaired cortico-DMS LTP, as well as decreased NMDAR mediated currents in the dorsomedial striatum were also detected. Taken together, our findings demonstrate for the first time that striatal GluN2B subunit plays an important role in the dorsal striatum-related motor skill learning and S-R learning and provide further evidence that the cortico-DMS LTP underlies dorsal striatum-related motor skill learning and S-R learning.