Architecture of integrated solid-state zinc-ion battery based on sodium alginate gelation.

How to construct a new electrode/electrolyte interface structure in solid-state batteries (SSBs), enhance interface stability, and improve the cycling performance of SSBs is a great challenge for the development of SSBs. Here, an all-in-one "interface-free" structure was developed. This interfacial structure constructs a full-interface hydrogen bonding network through the abundant hydrogen bond donors and acceptors in the cathode and electrolyte to enhance the interfacial stability and avoid interfacial failure during charging and discharging, and generates cathode-electrolyte interface (CEI) in-situ to effectively regulate zinc ion transport. Square cells assembled in this structure are stabilized for 100 cycles at a current density of 0.1 mA cm-2. This integrated electrode provides a new idea for the long stable cycle of SSBs.

Dendritic distribution of autophagosomes underlies pathway-selective induction of LTD.

The mechanism of long-term depression (LTD), a cellular substrate for learning, memory, and behavioral flexibility, is extensively studied in Schaffer collateral (SC) synapses, with inhibition of autophagy identified as a key factor. SC inputs terminate at basal and proximal apical dendrites, whereas distal apical dendrites receive inputs from the temporoammonic pathway (TAP). Here, we demonstrate that TAP and SC synapses have a shared LTD mechanism reliant on NMDA receptors, caspase-3, and autophagy inhibition. Despite this shared LTD mechanism, proximal apical dendrites contain more autophagosomes than distal apical dendrites. Additionally, unlike SC LTD, which diminishes with age, TAP LTD persists into adulthood. Our previous study shows that the high autophagy in adulthood disallows SC LTD induction. The reduction of autophagosomes from proximal to distal dendrites, combined with distinct LTD inducibility at SC and TAP synapses, suggests a model where the differential distribution of autophagosomes in dendrites gates LTD inducibility at specific circuits.

CoOx nanoparticles loaded on carbon spheres with synergistic effects for effective inhibition of shuttle effect in Li-S batteries.

Lithium-sulfur (Li-S) batteries, as one of the new energy storage batteries, show immense potential due to their high theoretical specific capacity and theoretical energy density. However, there are still some problems to be solved, among which the shuttle effect of lithium polysulfides is one extremely serious issue with respect to the industrial application of Li-S batteries. Rational design of electrode materials with effective catalytic conversion ability is an effective route to accelerate the conversion of lithium polysulfides (LiPSs). Herein, considering the adsorption and catalysis of LiPSs, CoOx nanoparticles (NPs) loaded on carbon sphere composites (CoOx/CS) were designed and constructed as cathode materials. The CoOx NPs obtained, with ultralow weight ratio and uniform distribution, consist of CoO, Co3O4, and metallic Co. The polar CoO and Co3O4 enable chemical adsorption towards LiPSs through Co-S coordination, and the conductive metallic Co can improve electronic conductivity and reduce impedance, which is beneficial for ion diffusion at the cathode. Based on these synergistic effects, the CoOx/CS electrode exhibits accelerated redox kinetics and enhanced catalytic activity for conversion of LiPSs. Consequently, the CoOx/CS cathode delivers improved cycling performance, with an initial capacity of 980.8 mA h g-1 at 0.1C and a reversible specific capacity of 408.4 mA h g-1 after 200 cycles, along with enhanced rate performance. This work provides a facile route to construct cobalt-based catalytic electrodes for Li-S batteries, and promotes understanding of the LiPSs conversion mechanism.

Analysis of Th-cell subsets in local and systemic environments from experimental periodontitis rats.

OBJECTIVES: The objective of this study was to explore the effect of periodontitis on Th-cell subsets in local and systemic environments. METHODS: A total of 32 male Sprague-Dawley rats were randomly divided into periodontitis and control groups. Silk ligatures were applied to the mandibular first (M1) molars in the periodontitis group. Inflammation and alveolar bone loss around the M1 molars were analyzed by histological staining and microcomputed tomography. The mRNA expression of interferon-γ (IFN-γ), interleukin 4 (IL-4), IL-17, and IL-10 in the gingiva was measured by qRT-PCR. The proportions of Th1, Th2, Th17, and Treg cells in the submandibular lymph nodes, peripheral blood, and jaw bone marrow were tested using flow cytometry. RESULTS: More inflammatory cells and alveolar bone resorption were found in the periodontitis group, with upregulated mRNA expression of IFN-γ, IL-17, and IL-10. The proportion of Th1 and Th17 cells was significantly elevated in submandibular lymph nodes, and the proportion of Th1, Th2, and Th17 cells was significantly elevated in peripheral blood, while the proportion of Th1, Th17, and Treg cells was significantly elevated in jaw bone marrow in the periodontitis group. CONCLUSION: This study suggests that periodontitis affects the differentiation of Th-cell subsets in both local and systemic environments, resulting in an increased proportion of proinflammatory cells.

Cobalt Nanoparticles Loaded on MXene for Li-S Batteries: Anchoring Polysulfides and Accelerating Redox Reactions.

Catalysis is regarded as an effective strategy to fundamentally increase sulfur utilization, accelerating the kinetics of the transformation between lithium polysulfides (LiPSs) and lithium sulfide (Li2 S) on a substrate. However, the intermodulation of catalysts and sulfur species is elusive, which is limited to the comprehensive analysis of electrochemical performance in the dynamic reaction process. Herein, cobalt nanoparticles loaded on MXene nanosheets (Co/Ti2 C) are selected as sulfur hosts and the representative catalyst. By combining ex situ electrochemical results and interfacial structural chemical monitoring, the catalysis process of Co/Ti2 C toward LiPSs conversion is revealed, and the outstanding performance originates from the optimization of chemical adsorption, catalytic activity, and lithium-ion transfer behaviors, which is based on electronic/ion modulation and sufficient interfaces among catalysts and electrolyte. This work can guide the construction of electronic modulation at triple-phase interface catalysis to overcome the shuttle effect and facilitate sulfur redox kinetics in Li-S batteries.

BAX regulates dendritic spine development via mitochondrial fusion.

BAX is a Bcl-2 family protein acting on apoptosis. It also promotes mitochondrial fusion by interacting with the mitochondrial fusion protein Mitofusin (Mfn1 and Mfn2). Neuronal mitochondria are important for the development and modification of dendritic spines, which are subcellular compartments accommodating excitatory synapses in postsynaptic neurons. The abundance of dendritic mitochondria influences dendritic spine development. Mitochondrial fusion is essential for mitochondrial homeostasis. Here, we show that in the hippocampal neuron of BAX knockout mice, mitochondrial fusion is impaired, leading to decreases in mitochondrial length and total mitochondrial mass in dendrites. Notably, BAX knockout mice also have fewer dendritic spines and less cellular Adenosine 5'triphosphate (ATP) in dendrites. The spine and ATP changes are abolished by restoring mitochondria fusion via overexpressing Mfn1 and Mfn2. These findings indicate that BAX-mediated mitochondrial fusion in neurons is crucial for the development of dendritic spines and the maintenance of cellular ATP levels.

Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts.

BACKGROUND: The odontogenic jaw cyst is a cavity containing liquid, semifluid or gaseous components, with the development of the disease. In recent years, with the rapid development of oral materials and the transformation of treatment of jaw cysts, more options are available for treatment of postoperative bone defect of jaw cysts. Guided bone regeneration (GBR) places biomaterials in the bone defect, and then uses biofilm to separate the proliferative soft tissue and the slow-growing bone tissue to maintain the space for bone regeneration, which is widely used in the field of implantology. AIM: To observe the clinical effect of GBR in repairing bone defect after enucleation of small and medium-sized odontogenic jaw cysts. METHODS: From June 2018 to September 2020, 13 patients (7 male, 6 female) with odontogenic jaw cysts were treated in the Department of Oral Surgery, Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine. Adults without hypertension, heart disease, diabetes or other systemic diseases were selected. The diagnosis was based on the final pathological results: 11 cases were diagnosed as apical cysts, one as primordial cyst, and one as dentigerous cyst. The lesions were located in the maxilla in seven cases, and in the mandible in six cases. All cases were treated with the same method of enucleation combined with GBR. RESULTS: Three to four months after the operation, the boundary between the implant site and the surrounding normal stroma was not obvious in patients with small-sized odontogenic jaw cysts. The patients with tooth defects were treated with implant after 6 mo. For the patients with medium-sized odontogenic jaw cysts, the density of the center of the implant area was close to the normal mass at 6 mo after surgery, and there was a clear boundary between the periphery of the implant area and the normal mass. The boundary between the periphery of the implant area and the normal mass was blurred at 8-9 mo after surgery. Patients with tooth defects were treated with implants at > 6 mo after the operation. CONCLUSION: Enucleation combined with guided bone regeneration in small and medium-sized odontogenic jaw cysts can shorten the time of osteogenesis, increase the amount of new bone formation, reduce complications, and improve quality of life.

Mitophagy in the basolateral amygdala mediates increased anxiety induced by aversive social experience.

Psychosocial stress is a common risk factor for anxiety disorders. The cellular mechanism for the anxiogenic effect of psychosocial stress is largely unclear. Here, we show that chronic social defeat (CSD) stress in mice causes mitochondrial impairment, which triggers the PINK1-Parkin mitophagy pathway selectively in the amygdala. This mitophagy elevation causes excessive mitochondrial elimination and consequent mitochondrial deficiency. Mitochondrial deficiency in the basolateral amygdalae (BLA) causes weakening of synaptic transmission in the BLA-BNST (bed nucleus of the stria terminalis) anxiolytic pathway and increased anxiety. The CSD-induced increase in anxiety-like behaviors is abolished in Pink1-/- and Park2-/- mice and alleviated by optogenetic activation of the BLA-BNST synapse. This study identifies an unsuspected role of mitophagy in psychogenetic-stress-induced anxiety elevation and reveals that mitochondrial deficiency is sufficient to increase anxiety and underlies the psychosocial-stress-induced anxiety increase. Mitochondria and mitophagy, therefore, can be potentially targeted to ameliorate anxiety.

Dysbindin-1 regulates mitochondrial fission and gamma oscillations.

Mitochondria are cellular ATP generators. They are dynamic structures undergoing fission and fusion. While much is known about the mitochondrial fission machinery, the mechanism of initiating fission and the significance of fission to neurophysiology are largely unclear. Gamma oscillations are synchronized neural activities that impose a great energy challenge to synapses. The cellular mechanism of fueling gamma oscillations has yet to be defined. Here, we show that dysbindin-1, a protein decreased in the brain of individuals with schizophrenia, is required for neural activity-induced fission by promoting Drp1 oligomerization. This process is engaged by gamma-frequency activities and in turn, supports gamma oscillations. Gamma oscillations and novel object recognition are impaired in dysbindin-1 null mice. These defects can be ameliorated by increasing mitochondrial fission. These findings identify a molecular mechanism for activity-induced mitochondrial fission, a role of mitochondrial fission in gamma oscillations, and mitochondrial fission as a potential target for improving cognitive functions.

The BAD-BAX-Caspase-3 Cascade Modulates Synaptic Vesicle Pools via Autophagy.

The BAD-BAX-caspase-3 cascade is a canonical apoptosis pathway. Macroautophagy ("autophagy" hereinafter) is a process by which organelles and aggregated proteins are delivered to lysosomes for degradation. Here, we report a new function of the BAD-BAX-caspase-3 cascade and autophagy in the control of synaptic vesicle pools. We found that, in hippocampal neurons of male mice, the BAD-BAX-caspase-3 pathway regulates autophagy, which in turn limits the size of synaptic vesicle pools and influences the kinetics of activity-induced depletion and recovery of synaptic vesicle pools. Moreover, the caspase-autophagy pathway is engaged by fear conditioning to facilitate associative fear learning and memory. This work identifies a new mechanism for controlling synaptic vesicle pools, and a novel, nonapoptotic, presynaptic function of the BAD-BAX-caspase-3 cascade.SIGNIFICANCE STATEMENT Despite the importance of synaptic vesicles for neurons, little is known about how the size of synaptic vesicle pools is maintained under basal conditions and regulated by neural activity. This study identifies a new mechanism for the control of synaptic vesicle pools, and a new, nonapoptotic function of the BAD-BAX-caspase-3 pathway in presynaptic terminals. Additionally, it indicates that autophagy is not only a homeostatic mechanism to maintain the integrity of cells and tissues, but also a process engaged by neural activity to regulate synaptic vesicle pools for optimal synaptic responses, learning, and memory.

Autophagy controls the induction and developmental decline of NMDAR-LTD through endocytic recycling.

NMDA receptor-dependent long-term depression (NMDAR-LTD) is a long-lasting form of synaptic plasticity. Its expression is mediated by the removal of AMPA receptors from postsynaptic membranes. Under basal conditions, endocytosed AMPA receptors are rapidly recycled back to the plasma membrane. In NMDAR-LTD, however, they are diverted to late endosomes for degradation. The mechanism for this switch is largely unclear. Additionally, the inducibility of NMDAR-LTD is greatly reduced in adulthood. The underlying mechanism and physiological significance of this phenomenon are elusive. Here, we report that autophagy inhibition is essential for the induction and developmental dampening of NMDAR-LTD. Autophagy is inhibited during NMDAR-LTD to decrease endocytic recycling. Autophagy inhibition is both necessary and sufficient for LTD induction. In adulthood, autophagy is up-regulated to make LTD induction harder, thereby preventing the adverse effect of excessive LTD on memory consolidation. These findings reveal the unrecognized functions of autophagy in synaptic plasticity, endocytic recycling, and memory.

Potentiation of Divergent Medial Amygdala Pathways Drives Experience-Dependent Aggression Escalation.

Heightened aggression can be serious concerns for the individual and society at large and are symptoms of many psychiatric illnesses, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression increase, however, are poorly understood. Here we find that prior attack experience leading to an increase in aggressive behavior, known as aggression priming, activates neurons within the posterior ventral segment of the medial amygdala (MeApv). Optogenetic stimulation of MeApv using a synaptic depression protocol suppresses aggression priming, whereas high-frequency stimulation enhances aggression, mimicking attack experience. Interrogation of the underlying neural circuitry revealed that the MeApv mediates aggression priming via synaptic connections with the ventromedial hypothalamus (VmH) and bed nucleus of the stria terminalis (BNST). These pathways undergo NMDAR-dependent synaptic potentiation after attack. Furthermore, we find that the MeApv-VmH synapses selectively control attack duration, whereas the MeApv-BNST synapses modulate attack frequency, both with no effect on social behavior. Synaptic potentiation of the MeApv-VmH and MeApv-BNST pathways contributes to increased aggression induced by traumatic stress, and weakening synaptic transmission at these synapses blocks the effect of traumatic stress on aggression. These results reveal a circuit and synaptic basis for aggression modulation by experience that can be potentially leveraged toward clinical interventions.SIGNIFICANCE STATEMENT Heightened aggression can have devastating social consequences and may be associated with psychiatric disorders, such as post-traumatic stress disorder. The circuit and synaptic mechanisms underlying experience-induced aggression escalation, however, are poorly understood. Here we identify two aggression pathways between the posterior ventral segment of the medial amygdala and its downstream synaptic partners, the ventromedial hypothalamus and bed nucleus of the stria terminalis that undergo synaptic potentiation after attack and traumatic stress to enhance aggression. Notably, weakening synaptic transmission in these circuits blocks aggression priming, naturally occurring aggression, and traumatic stress-induced aggression increase. These results illustrate a circuit and synaptic basis of aggression modulation by experience, which can be potentially targeted for clinical interventions.

Clinical significance of nuclear localisation of agrin in lung adenocarcinoma.

Agrin has recently been identified as a novel oncogene that is overexpressed in several types of human cancers. However, its role in lung cancer has not yet been investigated. The purpose of the current study was to investigate agrin protein expression in lung cancer and evaluate its clinicopathological and prognostic significance. In this study, A total of 86 lung adenocarcinoma samples paired with adjacent non-tumour tissue samples and eight lung adenocarcinoma non-paired samples were selected for immunohistochemical staining for agrin. Strong staining of agrin in nuclei of lung adenocarcinoma tissues was observed, but not in the nuclei of normal lung tissues (p < 0.001). Consistent with staining in lung adenocarcinoma tissues, the nuclei staining of agrin was also detected in lung cancer cell lines by immunofluorescence. This is the first report demonstrating that agrin is highly expressed in nuclei of lung adenocarcinoma tissues and that it is strongly correlated with lymph node metastasis (p = 0.002), clinical stage (p = 0.024), and poor differentiation (p = 0.022). Agrin-positive nuclear staining of lung adenocarcinoma cells could be used to identify greatly increased risk of metastasis in patients after surgery, which might serve as a valuable prognostic marker.

Effects of the presence and absence of amino acids on translation, signaling, and long-term depression in hippocampal slices from Fmr1 knockout mice.

Fragile X syndrome (FXS) is caused by silencing of the FMR1 gene and consequent absence of its protein product, fragile X mental retardation protein (FMRP). FMRP is an RNA-binding protein that can suppress translation. The absence of FMRP leads to symptoms of FXS including intellectual disability and has been proposed to lead to abnormalities in synaptic plasticity. Synaptic plasticity, protein synthesis, and cellular growth pathways have been studied extensively in hippocampal slices from a mouse model of FXS (Fmr1 KO). Enhanced metabotropic glutamate receptor 5 (mGluR5)-dependent long-term depression (LTD), increased rates of protein synthesis, and effects on signaling molecules have been reported. These phenotypes were found under amino acid starvation, a condition that has widespread, powerful effects on activation and translation of proteins involved in regulating protein synthesis. We asked if this non-physiological condition could have effects on Fmr1 KO phenotypes reported in hippocampal slices. We performed hippocampal slice experiments in the presence and absence of amino acids. We measured rates of incorporation of a radiolabeled amino acid into protein to determine protein synthesis rates. By means of western blots, we assessed relative levels of total and phosphorylated forms of proteins involved in signaling pathways regulating translation. We measured evoked field potentials in area CA1 to assess the strength of the long-term depression response to mGluR activation. In the absence of amino acids, we replicate many of the reported findings in Fmr1 KO hippocampal slices, but in the more physiological condition of inclusion of amino acids in the medium, we did not find evidence of enhanced mGluR5-dependent LTD. Activation of mGluR5 increased protein synthesis in both wild type and Fmr1 KO. Moreover, mGluR5 activation increased eIF2α phosphorylation and decreased phosphorylation of p70S6k in slices from Fmr1 KO. We propose that the eIF2α response is a cellular attempt to compensate for the lack of regulation of translation by FMRP. Our findings call for a re-examination of the mGluR theory of FXS.

MiR-27a targets DKK2 and SFRP1 to promote reosseointegration in the regenerative treatment of peri-implantitis.

In the inflamed microenvironment of peri-implantitis, limited osteogenesis on the implant surface impedes well-established reosseointegration using current clinical therapies. MicroRNAs (miRNAs) function as potent molecular managers that may simultaneously regulate multiple endogenous processes such as inflammation and osteogenesis. The delivery of miRNAs may provide a way to effectively treat some diseases. In this study, we showed that miR-27a was differentially downregulated in samples from a canine peri-implantitis model. We found that overexpressing miR-27a positively regulated osteogenesis-angiogenesis coupling by ameliorating the TNF-α inhibition of bone formation in vitro. Mechanistically, we identified Dickkopf2 (DKK2) and secreted frizzled related protein 1 (SFRP1) as two essential direct miR-27a targets that were osteogenic and angiogenic. Furthermore, we constructed a miR-27a-enhanced delivery system to repair the bone defect around implants in a canine peri-implantitis model. The results demonstrated that the miR-27a-treated group could optimize new bone formation and reosseointegration in vivo. Our assay provides evidence that this strategy exerts therapeutic effects on peri-implantitis, suggesting that it represents a feasible method to maintain the stability and masticatory function of dental implants. © 2018 American Society for Bone and Mineral Research.

MicroRNA sequence analysis identifies microRNAs associated with peri-implantitis in dogs.

Peri-implantitis, which is characterized by dense inflammatory infiltrates and increased osteoclast activity, can lead to alveolar bone destruction and implantation failure. miRNAs participate in the regulation of various inflammatory diseases, such as periodontitis and osteoporosis. Therefore, the present study aimed to investigate the differential expression of miRNAs in canine peri-implantitis and to explore the functions of their target genes. An miRNA sequence analysis was used to identify differentially expressed miRNAs in peri-implantitis. Under the criteria of a fold-change >1.5 and P<0.01, 8 up-regulated and 30 down-regulated miRNAs were selected for predictions of target genes and their biological functions. Based on the results of Gene Ontology (GO) and KEGG pathway analyses, these miRNAs may fine-tune the inflammatory process in peri-implantitis through an intricate mechanism. The results of quantitative real-time PCR (qRT-PCR) revealed that let-7g, miR-27a, and miR-145 may play important roles in peri-implantitis and are worth further investigation. The results of the present study provide insights into the potential biological effects of the differentially expressed miRNAs, and specific enrichment of target genes involved in the mitogen-activated protein kinase (MAPK) signaling pathway was observed. These findings highlight the intricate and specific roles of miRNAs in inflammation and osteoclastogenesis, both of which are key aspects of peri-implantitis, and thus may contribute to future investigations of the etiology, underlying mechanism, and treatment of peri-implantitis.

miR-26a and miR-384-5p are required for LTP maintenance and spine enlargement.

Long-term potentiation (LTP) is a form of synaptic plasticity that results in enhanced synaptic strength. It is associated with the formation and enlargement of dendritic spines-tiny protrusions accommodating excitatory synapses. Both LTP and spine remodelling are crucial for brain development, cognition and the pathophysiology of neurological disorders. The role of microRNAs (miRNAs) in the maintenance of LTP, however, is not well understood. Using next-generation sequencing to profile miRNA transcriptomes, we demonstrate that miR-26a and miR-384-5p specifically affect the maintenance, but not induction, of LTP and different stages of spine enlargement by regulating the expression of RSK3. Using bioinformatics, we also examine the global effects of miRNA transcriptome changes during LTP on gene expression and cellular activities. This study reveals a novel miRNA-mediated mechanism for gene-specific regulation of translation in LTP, identifies two miRNAs required for long-lasting synaptic and spine plasticity and presents a catalogue of candidate 'LTP miRNAs'.

NMDA receptor-dependent LTD is required for consolidation but not acquisition of fear memory.

NMDA receptor-dependent long-term depression (NMDAR-LTD) is a form of synaptic plasticity leading to long-lasting decreases in synaptic strength. NMDAR-LTD is essential for spatial and working memory, but its role in hippocampus-dependent fear memory has yet to be determined. Induction of NMDAR-LTD requires the activation of caspase-3 by cytochrome c. Cytochrome c normally resides in mitochondria and during NMDAR-LTD is released from mitochondria, a process promoted by Bax (Bcl-2-associated X protein). Bax induces cell death in apoptosis, but it plays a nonapoptotic role in NMDAR-LTD. Here, we investigated the role of NMDAR-LTD in fear memory in CA1-specific Bax knock-out mice. In hippocampal slices from these knock-out mice, while long-term potentiation of synaptic transmission, basal synaptic transmission, and paired-pulse ratio are intact, LTD in both young and fear-conditioned adult mice is obliterated. Interestingly, in CA1-specific Bax knock-out mice, long-term contextual fear memory is impaired, but the acquisition of fear memory and innate fear are normal. Moreover, these conditional Bax knock-out mice exhibit less behavioral despair. These findings indicate that NMDAR-LTD is required for consolidation, but not the acquisition of fear memory. Our study also shows that Bax plays an important role in depressive behavior.

miR-191 and miR-135 are required for long-lasting spine remodelling associated with synaptic long-term depression.

Activity-dependent modification of dendritic spines, subcellular compartments accommodating postsynaptic specializations in the brain, is an important cellular mechanism for brain development, cognition and synaptic pathology of brain disorders. NMDA receptor-dependent long-term depression (NMDAR-LTD), a prototypic form of synaptic plasticity, is accompanied by prolonged remodelling of spines. The mechanisms underlying long-lasting spine remodelling in NMDAR-LTD, however, are largely unclear. Here we show that LTD induction causes global changes in miRNA transcriptomes affecting many cellular activities. Specifically, we show that expression changes of miR-191 and miR-135 are required for maintenance but not induction of spine restructuring. Moreover, we find that actin depolymerization and AMPA receptor exocytosis are regulated for extended periods of time by miRNAs to support long-lasting spine plasticity. These findings reveal a miRNA-mediated mechanism and a role for AMPA receptor exocytosis in long-lasting spine plasticity, and identify a number of candidate miRNAs involved in LTD.

Electrophysiological effects of SKF83959 on hippocampal CA1 pyramidal neurons: potential mechanisms for the drug's neuroprotective effects.

Although the potent anti-parkinsonian action of the atypical D1-like receptor agonist SKF83959 has been attributed to the selective activation of phosphoinositol(PI)-linked D1 receptor, whereas the mechanism underlying its potent neuroprotective effect is not fully understood. In the present study, the actions of SKF83959 on neuronal membrane potential and neuronal excitability were investigated in CA1 pyramidal neurons of rat hippocampal slices. SKF83959 (10-100 µM) caused a concentration-dependent depolarization, associated with a reduction of input resistance in CA1 pyramidal neurons. The depolarization was blocked neither by antagonists for D1, D2, 5-HT(2A/2C) receptors and α1-adrenoceptor, nor by intracellular dialysis of GDP-ß-S. However, the specific HCN channel blocker ZD7288 (10 µM) antagonized both the depolarization and reduction of input resistance caused by SKF83959. In voltage-clamp experiments, SKF83959 (10-100 µM) caused a concentration-dependent increase of Ih current in CA1 pyramidal neurons, which was independent of D1 receptor activation. Moreover, SKF83959 (50 µM) caused a 6 mV positive shift in the activation curve of Ih and significantly accelerated the activation of Ih current. In addition, SKF83959 also reduced the neuronal excitability of CA1 pyramidal neurons, which was manifested by the decrease in the number and amplitude of action potentials evoked by depolarizing currents, and by the increase of firing threshold and rhoebase current. The above results suggest that SKF83959 increased Ih current through a D1 receptor-independent mechanism, which led to the depolarization of hippocampal CA1 pyramidal neurons. These findings provide a novel mechanism for the drug's neuroprotective effects, which may contributes to its therapeutic benefits in Parkinson's disease.