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As an excitatory transmitter system, the glutamatergic transmitter system controls excitability and conductivity of neurons. Since both cardiomyocytes and neurons are excitable cells, we hypothesized that cardiomyocytes may also be regulated by a similar system. Here, we have demonstrated that atrial cardiomyocytes have an intrinsic glutamatergic transmitter system, which regulates the generation and propagation of action potentials. First, there are abundant vesicles containing glutamate beneath the plasma membrane of rat atrial cardiomyocytes. Second, rat atrial cardiomyocytes express key elements of the glutamatergic transmitter system, such as the glutamate metabolic enzyme, ionotropic glutamate receptors (iGluRs), and glutamate transporters. Third, iGluR agonists evoke iGluR-gated currents and decrease the threshold of electrical excitability in rat atrial cardiomyocytes. Fourth, iGluR antagonists strikingly attenuate the conduction velocity of electrical impulses in rat atrial myocardium both in vitro and in vivo. Knockdown of GRIA3 or GRIN1, two highly expressed iGluR subtypes in atria, drastically decreased the excitatory firing rate and slowed down the electrical conduction velocity in cultured human induced pluripotent stem cell (iPSC)-derived atrial cardiomyocyte monolayers. Finally, iGluR antagonists effectively prevent and terminate atrial fibrillation in a rat isolated heart model. In addition, the key elements of the glutamatergic transmitter system are also present and show electrophysiological functions in human atrial cardiomyocytes. In conclusion, our data reveal an intrinsic glutamatergic transmitter system directly modulating excitability and conductivity of atrial cardiomyocytes through controlling iGluR-gated currents. Manipulation of this system may open potential new avenues for therapeutic intervention of cardiac arrhythmias.

Aberrant regulation of microRNAs (miRNAs) has been implicated in the pathogenesis of Alzheimer’s disease (AD), but most abnormally expressed miRNAs found in AD are not regulated by synaptic activity. Here we report that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in a mouse model of AD. miR-135a-5p levels are significantly reduced in excitatory hippocampal neurons of AD model mice. This decrease is tau dependent and mediated by Foxd3. Inhibition of miR-135a-5p leads to synaptic disorder and memory impairments. Furthermore, excess Rock2 levels caused by loss of miR-135a-5p plays an important role in the synaptic disorder of AD via phosphorylation of Ser726 on adducin 1 (Add1). Blocking the phosphorylation of Ser726 on Add1 with a membrane-permeable peptide effectively rescues the memory impairments in AD mice. Taken together, these findings demonstrate that synaptic-related miR-135a-5p mediates synaptic/memory deficits in AD via the Rock2/Add1 signaling pathway, illuminating a potential therapeutic strategy for AD., Several micro RNAs have been shown to be deregulated in brain tissue or sera from individuals with Alzheimer’s disease and in AD mouse models. The authors show that miR-135a-5p is downregulated in excitatory pyramidal neurons from AD mice and that dysfunction of miR-135a-5p/Rock2/Add1 results in memory/synaptic disorder in AD.

Iron homeostasis disturbance has been implicated in Alzheimer’s disease (AD), and excess iron exacerbates oxidative damage and cognitive defects. Ferroptosis is a nonapoptotic form of cell death dependent upon intracellular iron. However, the involvement of ferroptosis in the pathogenesis of AD remains elusive. Here, we report that ferroportin1 (Fpn), the only identified mammalian nonheme iron exporter, was downregulated in the brains of APPswe/PS1dE9 mice as an Alzheimer’s mouse model and Alzheimer’s patients. Genetic deletion of Fpn in principal neurons of the neocortex and hippocampus by breeding Fpnfl/fl mice with NEX-Cre mice led to AD-like hippocampal atrophy and memory deficits. Interestingly, the canonical morphological and molecular characteristics of ferroptosis were observed in both Fpnfl/fl/NEXcre and AD mice. Gene set enrichment analysis (GSEA) of ferroptosis-related RNA-seq data showed that the differentially expressed genes were highly enriched in gene sets associated with AD. Furthermore, administration of specific inhibitors of ferroptosis effectively reduced the neuronal death and memory impairments induced by Aβ aggregation in vitro and in vivo. In addition, restoring Fpn ameliorated ferroptosis and memory impairment in APPswe/PS1dE9 mice. Our study demonstrates the critical role of Fpn and ferroptosis in the progression of AD, thus provides promising therapeutic approaches for this disease.

Background Aldh1a1 neurons are a subtype of gamma-aminobutyric acid (GABA) inhibitory neurons that use Aldh1a1 rather than glutamate decarboxylase (GAD) as an enzyme for synthesizing GABA transmitters. However, the behaviors and circuits of this newly identified subtype of inhibitory interneurons remain unknown. Methods We generated a mutant mouse line in which cyclization recombination enzyme (CRE) was expressed under the control of the Aldh1a1 promotor (Aldh1a1-CRE mice). Using this mutant strain of mice together with the heterozygous male Alzheimer’s disease (AD) related model mice (APPswe/PSEN1dE9, or AD mice) and a genetically modified retrograde and anterograde synaptic tracing strategy, we have studied a specific synaptic circuit of Aldh1a1 neurons with system-level function and disease progression in AD mice. Results We demonstrate that Aldh1a1 neurons encode delay of gratification that measures self-control skills in decision making by projecting inhibitory synapses directly onto excitatory glutamate neurons in the intermediate lateral septum (EGNIS) and receiving synaptic inputs from layer 5b pyramidal neurons in the medial prefrontal cortex (L5PN). L5PN → Aldh1a1 synaptic transmission undergoes long-term potentiation (LTP). Pathway specific inhibition by either genetic silencing presynaptic terminals or antagonizing postsynaptic receptors impairs delay of gratification, resulting in the impulsive behaviors. Further studies show that reconstitution of Aldh1a1-deficient neurons with the expression of exogenous Aldh1a1 (eAldh1a1) restores Aldh1a1 → EGNIS synaptic transmission and rescues the impulsive behaviors in AD mice. Conclusions These results not only identify a specific function and circuit of Aldh1a1 neurons but also provide a cellular point of entry to an important but understudied synaptic mechanism for the induction of impulsive behaviors at an early stage of AD.

Communicating hydrocephalus (CH) is a common neurological disorder caused by a blockage of cerebrospinal fluid. In this study, we aimed to explore the potential molecular mechanism underlying CH development. Quantitative proteomic analysis was performed to screen the differentially expressed proteins (DEPs) between patients with and without CH. A CH rat model was verified by Hoechst staining, and the co-localization of the target protein and neuron was detected using immunofluorescence staining. Loss-of-function experiments were performed to examine the effect of KLK6 on the synapse structure. A total of 11 DEPs were identified, and kallikrein 6 (KLK6) expression was found to be significantly upregulated in patients with CH compared with that in patients without CH. The CH rat model was successfully constructed, and KLK6 was found to be co-localized with neuronal nuclei in brain tissue. The expression level of KLK6 in the CH group was higher than that in the control group. After interference of KLK6 expression, the expression levels of synapsin-1 and PSD95 in neuronal cells were increased, and the length, number, and structure of synapses were significantly improved. The transcriptome profile (PRJNA719985) after interference of KLK6 expression was obtained, and 5,681 differentially expressed genes (DEGs) were identified. The upregulated DEGs of Appl2, Nav2, and Nrn1 may be involved in the recovery of synaptic structures after interference of KLK6 expression. Collectively, KLK6 participates in the development of CH and might provide a new target for CH treatment.

Background Death-associated protein kinase 1 (DAPK1) is a widely distributed serine/threonine kinase that is critical for cell death in multiple neurological disorders, including Alzheimer’s disease and stroke. However, little is known about the role of DAPK1 in the pathogenesis of Parkinson’s disease (PD), the second most common neurodegenerative disorder. Methods We used Western blot and immunohistochemistry to evaluate the alteration of DAPK1. Quantitative polymerase chain reaction and fluorescence in situ hybridization were used to analyze the expression of microRNAs in PD mice and patients with PD. Rotarod, open field, and pole tests were used to evaluate the locomotor ability. Immunofluorescence, Western blot, and filter traps were used to evaluate synucleinopathy in PD mice. Results We found that DAPK1 is posttranscriptionally upregulated by a reduction in microRNA-26a (miR-26a) caused by a loss of the transcription factor CCAAT enhancer-binding protein alpha. The overexpression of DAPK1 in PD mice is positively correlated with neuronal synucleinopathy. Suppressing miR-26a or upregulating DAPK1 results in synucleinopathy, dopaminergic neuron cell death, and motor disabilities in wild-type mice. In contrast, genetic deletion of DAPK1 in dopaminergic neurons by crossing DAT-Cre mice with DAPK1 floxed mice effectively rescues the abnormalities in mice with chronic MPTP treatment. We further showed that DAPK1 overexpression promotes PD-like phenotypes by direct phosphorylation of α-synuclein at the serine 129 site. Correspondingly, a cell-permeable competing peptide that blocks the phosphorylation of α-synuclein prevents motor disorders, synucleinopathy, and dopaminergic neuron loss in the MPTP mice. Conclusions miR-26a/DAPK1 signaling cascades are essential in the formation of the molecular and cellular pathologies in PD.

Background Hyperhomocysteinemia is an independent risk factor for dementia, including Alzheimer’s disease. Lowering homocysteine levels with folic acid treatment with or without vitamin B12 has shown few clinical benefits on cognition. Methods To verify the effect of emodin, a naturally active compound from Rheum officinale, on hyperhomocysteinemia-induced dementia, rats were treated with homocysteine injection (HCY, 400 μg/kg/d, 2 weeks) via vena caudalis. Afterwards, HCY rats with cognitive deficits were administered intragastric emodin at different concentrations for 2 weeks: 0 (HCY-E0), 20 (HCY-E20), 40 (HCY-E40), and 80 mg/kg/d (HCY-E80). Results β-Amyloid overproduction, tau hyperphosphorylation, and losses of neuron and synaptic proteins were detected in the hippocampi of HCY-E0 rats with cognitive deficits. HCY-E40 and HCY-E80 rats had better behavioral performance. Although it did not reduce the plasma homocysteine level, emodin (especially 80 mg/kg/d) reduced the levels of β-amyloid and tau phosphorylation, decreased the levels of β-site amyloid precursor protein-cleaving enzyme 1, and improved the activity of protein phosphatase 2A. In the hippocampi of HCY-E40 and HCY-E80 rats, the neuron numbers, levels of synaptic proteins, and phosphorylation of the cAMP responsive element-binding protein at Ser133 were increased. In addition, depressed microglial activation and reduced levels of 5-lipoxygenase, interleukin-6, and tumor necrosis factor α were also observed. Lastly, hyperhomocysteinemia-induced microangiopathic alterations, oxidative stress, and elevated DNA methyltransferases 1 and 3β were rescued by emodin. Conclusions Emodin represents a novel potential candidate agent for hyperhomocysteinemia-induced dementia and Alzheimer’s disease-like features.

Cholinergic degeneration is one of the key pathological hallmarks of Alzheimer’s disease (AD), a condition that is characterized by synaptic disorders and memory impairments. Nerve growth factor (NGF) is secreted in brain regions that receive projections from the basal forebrain cholinergic neurons. The trophic effects of NGF rely on the appropriate maturation of NGF from its precursor, proNGF. The ratio of proNGF/NGF is known to be increased in patients with AD; however, the mechanisms that underlie this observation have yet to be elucidated. Here, we demonstrated that levels of miR-144-3p are increased in the hippocampi and the medial prefrontal cortex of an APP/PS1 mouse model of AD. These mice also exhibited cholinergic degeneration (including the loss of cholinergic fibers, the repression of choline acetyltransferase (ChAT) activity, the reduction of cholinergic neurons, and an increased number of dystrophic neurites) and synaptic/memory deficits. The elevated expression of miR-144-3p specifically targets the mRNA of tissue plasminogen activator (tPA) and reduces the expression of tPA, thus resulting in the abnormal maturation of NGF. The administration of miR-144-3p fully replicated the cholinergic degeneration and synaptic/memory deficits observed in the APP/PS1 mice. The injection of an antagomir of miR-144-3p into the hippocampi partially rescued cholinergic degeneration and synaptic/memory impairments by restoring the levels of tPA protein and by correcting the ratio of proNGF/NGF. Collectively, our research revealed potential mechanisms for the disturbance of NGF maturation and cholinergic degeneration in AD and identified a potential therapeutic target for AD.

Alzheimer's disease (AD), manifested by memory loss and a decline in cognitive functions, is the most prevalent neurodegenerative disease accounting for 60-80 % of dementia cases. But, to-date, there is no effective treatment available to slow or stop the progression of AD. Exosomes are small extracellular vesicles that carry constituents, such as functional messenger RNAs, non-coding RNAs, proteins, lipids, DNA, and other bioactive substances of their source cells. In the brain, exosomes are likely to be sourced by almost all cell types and involve in cell communication to regulate cellular functions. The yet, accumulated evidence on the roles of exosomes and their constituents in the AD pathological process suggests their significance as additional biomarkers and therapeutic targets for AD. This review summarizes the current reported research findings on exosomes roles in the pathogenesis, diagnosis, and treatment of AD.

Incidence of intracerebral hemorrhage (ICH) and brain iron accumulation increases with age. Excess iron accumulation in brain tissues post‐ICH induces oxidative stress and neuronal damage. However, the mechanisms underlying iron deregulation in ICH, especially in the aged ICH model have not been well elucidated. Ferroportin1 (Fpn) is the only identified nonheme iron exporter in mammals to date. In our study, we reported that Fpn was significantly upregulated in perihematomal brain tissues of both aged ICH patients and mouse model. Fpn deficiency induced by injecting an adeno‐associated virus (AAV) overexpressing cre recombinase into aged Fpn‐floxed mice significantly worsened the symptoms post‐ICH, including hematoma volume, cell apoptosis, iron accumulation, and neurologic dysfunction. Meanwhile, aged mice pretreated with a virus overexpressing Fpn showed significant improvement of these symptoms. Additionally, based on prediction of website tools, expression level of potential miRNAs in ICH tissues and results of luciferase reporter assays, miR‐124 was identified to regulate Fpn expression post‐ICH. Higher serum miR‐124 levels were correlated with poor neurologic scores of aged ICH patients. Administration of miR‐124 antagomir enhanced Fpn expression and attenuated iron accumulation in aged mice model. Both apoptosis and ferroptosis, but not necroptosis, were regulated by miR‐124/Fpn signaling manipulation. Our study demonstrated the critical role of miR‐124/Fpn signaling in iron metabolism and neuronal death post‐ICH in aged murine model. Thus, Fpn upregulation or miR‐124 inhibition might be promising therapeutic approachs for this disease., Brain iron accumulation following ICH induced secondary brain injury and neuronal death. However, the mechanisms underlying iron deregulation in aged ICH model is poorly understood. miR‐124/Fpn signaling was downregulated in aged ICH model mice and patients as a protection mechanism. Higher serum miR‐124 levels were correlated with poor neurologic scores of aged patients. Targeting miR‐124/Fpn signaling could reduce the iron accumulation post‐ICH in aged murine model, thus ameliorated hematoma volume, cell apoptosis and neurologic dysfunction through inhibiting apoptosis and ferroptosis.

Recently, we have reported that dentate mossy cells (MCs) control memory precision via directly and functionally innervating local somatostatin (SST) inhibitory interneurons. Here, we report a discovery that dysfunction of synaptic transmission between MCs and SST cells causes memory imprecision in a mouse model of early Alzheimer's disease (AD). Single‐cell RNA sequencing reveals that miR‐128 that binds to a 3′UTR of STIM2 and inhibits STIM2 translation is increasingly expressed in MCs from AD mice. Silencing miR‐128 or disrupting miR‐128 binding to STIM2 evokes STIM2 expression, restores synaptic function, and rescues memory imprecision in AD mice. Comparable findings are achieved by directly engineering MCs with the expression of STIM2. This study unveils a key synaptic and molecular mechanism that dictates how memory maintains or losses its details and warrants a promising target for therapeutic intervention of memory decays in the early stage of AD., Memory is imprecise in an early stage of AD due to a selective degeneration of mossy cell synaptic transmission. MiR‐128 inhibition of STIM2 translation causes a selective degeneration of mossy cell synaptic transmission in an early stage of AD. Uncoupling miR‐128 binding to STIM2 induces STIM2 translation, restores mossy cell synaptic transmission, and rescues memory precision in AD mice.

Dominance hierarchy is a fundamental phenomenon in grouped animals and human beings, however, the underlying regulatory mechanisms remain elusive. Here, we report that an antisense long non-coding RNA (lncRNA) of synapsin II, named as AtLAS, plays a crucial role in the regulation of social hierarchy. AtLAS is decreased in the prefrontal cortical excitatory pyramidal neurons of dominant mice; consistently, silencing or overexpression of AtLAS increases or decreases the social rank, respectively. Mechanistically, we show that AtLAS regulates alternative polyadenylation of synapsin II gene and increases synapsin 2b (syn2b) expression. Syn2b reduces AMPA receptor (AMPAR)-mediated excitatory synaptic transmission through a direct binding with AMPAR at the postsynaptic site via its unique C-terminal sequence. Moreover, a peptide disrupting the binding of syn2b with AMPARs enhances the synaptic strength and social ranks. These findings reveal a novel role for lncRNA AtLAS and its target syn2b in the regulation of social behaviors by controlling postsynaptic AMPAR trafficking.

Long non-coding RNA (lncRNA) is a kind of non-coding RNA (ncRNA), with a length of 200 nt to 100 kb, that lacks a significant open reading frame (ORF) encoding a protein. lncRNAs are widely implicated in various physiological and pathological processes, such as epigenetic regulation, cell cycle regulation, cell differentiation regulation, cancer, and neurodegenerative diseases, through their interactions with chromatin, protein, and other RNAs. Numerous studies have suggested that lncRNAs are closely linked with the occurrence and development of a variety of diseases, especially neurodegenerative diseases, of which the etiologies are complicated and the underlying mechanisms remain elusive. Determining the roles of lncRNA in the pathogenesis of neurodegenerative diseases will not only deepen understanding of the physiological and pathological processes that occur in those diseases but also provide new ideas and solutions for their diagnosis and prevention. This review aims to highlight the progress of lncRNA research in the pathological and behavioral changes of neurodegenerative diseases. Specifically, we focus on how lncRNA dysfunctions are involved in the pathogenesis of Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis.

Aggregation of amyloid-β (Aβ) peptides, which are the cleavage products of amyloid precursor protein (APP), is a major pathological hallmark in the brain of Alzheimer's disease (AD). Now, we know little about the roles of APP translation in the disease progression of AD. Here, we show that BC1, a long noncoding RNA (lncRNA), is expressed in the brain of AD mice. BC1 induces APP mRNA translation via association with a fragile X syndrome protein (FMRP). Inhibition of BC1 or BC1-FMRP association in AD mice blocks aggregation of Aβ in the brain and protects against the spatial learning and memory deficits. Expression of exogenous BC1 in excitatory pyramidal neurons of mice induces Aβ peptides accumulation and the spatial learning and memory impairments. This study provides a novel mechanism underlying aggregation of Aβ peptides via BC1 induction of APP mRNA translation and hence warrants a promising target for AD therapy.

Choline acetyltransferase neurons in the vertical diagonal band of Broca (vChATs) degenerate in the early stage of Alzheimer’s disease (AD). Here, we report that vChATs directly innervate newly generated immature neurons (NGIs) in the dorsal hippocampus (dNGIs) of adult mice and regulate both the dNGIs survival and spatial pattern separation. In a mouse model that exhibits amyloid-β plaques similar to AD patients, cholinergic synaptic transmission, dNGI survival and spatial pattern separation are impaired. Activation of vChATs with theta burst stimulation (TBS) that alleviates the decay in cholinergic synaptic transmission effectively protects against spatial pattern separation impairments in the AD mice and this protection was completely abolished by inhibiting the dNGIs survival. Thus, the impairments of pattern separation-associated spatial memory in AD mice are in part caused by degeneration of cholinergic synaptic transmission that modulates the dNGIs survival., Cholinergic neurons in the diagonal band of Broca degenerate early in Alzheimer’s disease. Here the authors show that in healthy mice, these cholinergic inputs innervate newborn neurons in the hippocampus, and that loss of this innervation in an Alzheimer’s disease model leads to impairments in spatial memory.

Functional failure of tau contributes to age-dependent, iron-mediated neurotoxicity, and as iron accumulates in ischemic stroke tissue, we hypothesized that tau failure may exaggerate ischemia-reperfusion-related toxicity. Indeed, unilateral, transient middle cerebral artery occlusion (MCAO) suppressed hemispheric tau and increased iron levels in young (3-month-old) mice and rats. Wild-type mice were protected by iron-targeted interventions: ceruloplasmin and amyloid precursor protein ectodomain, as well as ferroptosis inhibitors. At this age, tau-knockout mice did not express elevated brain iron and were protected against hemispheric reperfusion injury following MCAO, indicating that tau suppression may prevent ferroptosis. However, the accelerated age-dependent brain iron accumulation that occurs in tau-knockout mice at 12 months of age negated the protective benefit of tau suppression against MCAO-induced focal cerebral ischemia-reperfusion injury. The protective benefit of tau knockout was revived in older mice by iron-targeting interventions. These findings introduce tau-iron interaction as a pleiotropic modulator of ferroptosis and ischemic stroke outcome.

Altered neurogenesis and disrupted expression of synaptic proteins in prefrontal cortex of SHANK3 -deficient non-human primate

Background Herpes simplex virus type 1 strain 129 (H129) has represented a promising anterograde neuronal circuit tracing tool, which complements the existing retrograde tracers. However, the current H129 derived tracers are multisynaptic, neither bright enough to label the details of neurons nor capable of determining direct projection targets as monosynaptic tracer. Methods Based on the bacterial artificial chromosome of H129, we have generated a serial of recombinant viruses for neuronal circuit tracing. Among them, H129-G4 was obtained by inserting binary tandemly connected GFP cassettes into the H129 genome, and H129-ΔTK-tdT was obtained by deleting the thymidine kinase (TK) gene and adding tdTomato coding gene to the H129 genome. Then the obtained viral tracers were tested in vitro and in vivo for the tracing capacity. Results H129-G4 is capable of transmitting through multiple synapses, labeling the neurons by green florescent protein, and visualizing the morphological details of the labeled neurons. H129-ΔTK-tdT neither replicates nor spreads in neurons alone, but transmits to and labels the postsynaptic neurons with tdTomato in the presence of complementary expressed TK from a helper virus. H129-ΔTK-tdT is also capable to map the direct projectome of the specific neuron type in the given brain regions in Cre transgenic mice. In the tested brain regions where circuits are well known, the H129-ΔTK-tdT tracing patterns are consistent with the previous results. Conclusions With the assistance of the helper virus complimentarily expressing TK, H129-ΔTK-tdT replicates in the initially infected neuron, transmits anterogradely through one synapse, and labeled the postsynaptic neurons with tdTomato. The H129-ΔTK-tdT anterograde monosynaptic tracing system offers a useful tool for mapping the direct output in neuronal circuitry. H129-G4 is an anterograde multisynaptic tracer with a labeling signal strong enough to display the details of neuron morphology. Electronic supplementary material The online version of this article (doi:10.1186/s13024-017-0179-7) contains supplementary material, which is available to authorized users.

Immediately following ischemia, glutamate accumulates in the extracellular space and results in extensive stimulation of its receptors including N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptors. A large amount of Ca2+ influx directly through the receptor-gated ion channels which leads to Ca2+ overload and triggers several downstream lethal reactions. As a result, cell dies via apoptosis or necrosis, or both. Death-associated protein kinase 1 (DAPK1) physically and functionally interacts with the NMDA receptor GluN2B subunit at extra-synaptic sites and this interaction acts as a central mediator for stroke damage. The goal of this study is to explore an effective strategy in the treatment of stroke with a molecular genetic manipulation to interrupt DAPK1-GluN2B interaction. We generated a mutant strain of mice with the conditional deletion of GluN2B C-terminal tail consisting of amino acids 886-1269 in the forebrain excitatory neurons (the GluN2B mutant mice) and tested the protective effects of this mutation in stroke damages. GluN2B mutation effectively disrupted the DAPK1-GluN2B interaction and inhibited extra-synaptic NMDA receptor currents without affecting synaptic NMDA receptor channel activity in the central neurons. GluN2B mutation protected against stroke damages both in vitro and in vivo and hence improved behavioral performance. Disruption of the DAPK1-GluN2B interaction is therapeutically effective against stroke damages.

Histone deacetylase 2 (HDAC2) plays a major role in the epigenetic regulation of gene expression. Previous studies have shown that HDAC2 expression is strongly increased in Alzheimer’s disease (AD), a major neurodegenerative disorder and the most common form of dementia. Moreover, previous studies have linked HDAC2 to Aβ overproduction in AD; however, its involvement in tau pathology and other memory-related functions remains unclear. Here, we show that increased HDAC2 levels strongly correlate with phosphorylated tau in a mouse model of AD. HDAC2 overexpression induced AD-like tau hyperphosphorylation and aggregation, which were accompanied by a loss of dendritic complexity and spine density. The ectopic expression of HDAC2 resulted in the deacetylation of the hepatocyte nuclear factor 4α (HNF-4A) transcription factor, which disrupted its binding to the miR-101b promoter. The suppression of miR-101b caused an upregulation of its target, AMP-activated protein kinase (AMPK). The introduction of miR-101b mimics or small interfering RNAs (siRNAs) against AMPK blocked HDAC2-induced tauopathy and dendritic impairments in vitro. Correspondingly, miR-101b mimics or AMPK siRNAs rescued tau pathology, dendritic abnormalities, and memory deficits in AD mice. Taken together, the current findings implicate the HDAC2/miR-101/AMPK pathway as a critical mediator of AD pathogenesis. These studies also highlight the importance of epigenetics in AD and provide novel therapeutic targets.

Excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) form functional excitatory synapses with CA1 parvalbumin inhibitory neurons (CA1PV) and undergo selective degeneration in the early stages of Alzheimer's disease (AD). Here, we show that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPNof AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PVsynaptic loss and improves spatial learning and memory in AD mice. This study demonstrates that activation of DAPK1 in ECIIPNcontributes to a memory loss in AD and hence warrants a promising target for the treatment of AD.SIGNIFICANCE STATEMENTOur recent study reported that excitatory pyramidal neurons in the entorhinal cortical layer II region (ECIIPN) target to CA1 parvalbumin-type inhibitory neurons (CA1PV) at a direct pathway and are one of the most vulnerable brain cells that are selectively degenerated in the early stage of Alzheimer's disease (AD). Our present study shows that death-associated protein kinase 1 (DAPK1) is selectively activated in ECIIPNof AD mice. Inhibition of DAPK1 by deleting a catalytic domain or a death domain of DAPK1 rescues the ECIIPN-CA1PVsynaptic loss and improves spatial learning and memory in the early stage of AD. These data not only demonstrate a crucial molecular event for synaptic degeneration but also provide a therapeutic target for the treatment of AD.

MicroRNAs have been implicated in diverse physiological and pathological processes. We previously reported that aberrant microRNA-124 (miR-124)/non-receptor-type protein phosphatase 1 (PTPN1) signaling plays an important role in the synaptic disorders associated with Alzheimer's disease (AD). In this study, we further investigated the potential role of miR-124/PTPN1 in the tau pathology of AD. We first treated the mice with intra-hippocampal stereotactic injections. Then, we used quantitative real-time reverse transcription PCR (qRT-PCR) to detect the expression of microRNAs. Western blotting was used to measure the level of PTPN1, the level of tau protein, the phosphorylation of tau at AD-related sites, and alterations in the activity of glycogen synthase kinase 3β (GSK-3β) and protein phosphatase 2 (PP2A). Immunohistochemistry was also used to detect changes in tau phosphorylation levels at AD-related sites and somadendritic aggregation. Soluble and insoluble tau protein was separated by 70% formic acid (FA) extraction to examine tau solubility. Finally, behavioral experiments (including the Morris water maze, fear conditioning, and elevated plus maze) were performed to examine learning and memory ability and emotion-related behavior. We found that artificially replicating the abnormalities in miR-124/PTPN1 signaling induced AD-like tau pathology in the hippocampus of wild-type mice, including hyperphosphorylation at multiple sites, insolubility and somadendritic aggregation, as well as learning/memory deficits. We also found that disruption of miR-124/PTPN1 signaling was caused by the loss of RE1-silencing transcription factor protein, which can be initiated by Aβ insults or oxidative stress, as observed in the brains of P301S mice. Correcting the deregulation of miR-124/PTPN1 signaling rescued the tau pathology and learning/memory impairments in the P301S mice. We also found that miR-124/PTPN1 abnormalities induced activation of glycogen synthase kinase 3 (GSK-3) and inactivation of protein phosphatase 2A (PP2A) by promoting tyrosine phosphorylation, implicating an imbalance in tau kinase/phosphatase. Thus, targeting the miR-124/PTPN1 signaling pathway is a promising therapeutic strategy for AD.

The present study aimed to identify microRNAs (miRNAs) that are involved in neuropathic pain and predict their corresponding roles in the pathogenesis and development process of neuropathic pain. The rat model of neuropathic pain caused by spared nerve injury (SNI) was established in Sprague-Dawley male rats, followed by small RNA sequencing of the L3–L6 dorsal root ganglion. Real-time PCR was performed to validate the differently expressed miRNAs. Functional verification was performed by intrathecally injecting the animals with miRNA agomir. A total of 72 differentially expressed miRNAs were identified in the SNI rats, including 33 upregulated and 39 downregulated miRNAs. The results of qPCR further verified the expression levels of rno-miR-6215 (P=0.015), rno-miR-1224 (P=0.030), rno-miR-1249 (P=0.038), and rno-miR-488-3p (P=0.048), which were all significantly downregulated in the SNI rats compared to the control ones. The majority of differentially expressed miRNAs were associated with phosphorylation, intracellular signal transduction, and cell death. Target prediction, Gene Ontology, and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses suggested that these differentially expressed miRNAs targeted genes that are related to axon guidance, focal adhesion, and Ras and Wnt signaling pathways. Moreover, miR-1224 agomir significantly alleviated SNI-induced neuropathic pain. The current findings provide new insights into the role of miRNAs in the pathogenesis of neuropathic pain.

Mossy cells (MCs) are a unique group of excitatory neurons in the hippocampus, a brain region important for emotion, learning, and memory. Due to the lack of a reliable method to isolate MCs from other cell types, how MCs integrate neural information and convey it to their synaptic targets for engaging a specific function are still unknown. Here, we report that MCs control the efficacy of spatial memory retrieval by synapsing directly onto local somatostatin-expressing (SST) cells. MC-SST synaptic transmission undergoes long-term potentiation (LTP), requiring Gria2-lacking Ca2+-permeable anti-α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA) receptor (Ca2+AR). A long noncoding RNA (Gria2I) is associated with Gria2 transcriptional repressors in SST cells. Silencing Gria2I induces Gria2 transcription, blocks LTP of MCs-SST synaptic transmission, and reduces the efficacy of memory retrieval. Thus, MCs directly and functionally innervate local SST neurons, and this innervation controls the efficacy of spatial memory retrieval by Gria2I inhibition of Gria2 transcription.

Stroke activates microglia pro-inflammatory response that not only induces the early neuronal injuries but also causes the secondary brain infarction. Yet, the underlying mechanisms for how microglia become activated in stroke are still unknown. Here, using the next-generation of RNA sequencing we find a total of 778 genes increasingly expressed in brain of stroke mice. Of these, we identified Hmgb2 as a microglia pro-inflammatory mediator by promoting the transcription of Ctss. Inhibition of either Hmgb2 or Ctss blocks microglia pro-inflammatory response and protects against brain damages and improves the neurological functions of stroke mice. This study uncovers Hmgb2 and Ctss as the major microglia inflammatory response mediators in stroke and hence warrants the promising targets for stroke therapies.

Death-associated protein kinase 1 (DAPK1), a Ca2+/calmodulin (CaM)-dependent serine/threonine protein kinase, plays important roles in diverse apoptosis pathways not only in tumor suppression but also in neuronal cell death. The requirement of DAPK1 catalytic activity for its proposed cell functions and the elevation of catalytic activity of DAPK1 in injured neurons in models of neurological diseases, such as ischemia and epilepsy, validate that DAPK1 can be taken as a potential therapeutic target in these diseases. Recent studies show that DAPK1-NR2B, DAPK1-DANGER, DAPK1-p53, and DAPK1-Tau are currently known pathways in stroke-induced cell death, and blocking these cascades in an acute treatment effectively reduces neuronal loss. In this review, we focus on the role of DAPK1 in neuronal cell death after stroke. We hope to provide exhaustive summaries of relevant studies on DAPK1 signals involved in stroke damage. Therefore, disrupting DAPK1-relevant cell death pathway could be considered as a promising therapeutic approach in stroke.

Tauopathies are a class of neurodegenerative diseases that are characterized by pathological aggregation of tau protein, which is accompanied by synaptic disorders. However, the role of tau in endocytosis, a fundamental process in synaptic transmission, remains elusive. Here, we report that forced expression of human tau (hTau) in mouse cortical neurons impairs endocytosis by decreasing the level of the GTPase dynamin 1 via disruption of the miR‐132‐MeCP2 pathway; this process can also be detected in the brains of Alzheimer's patients and hTau mice. Our results provide evidence for a novel role of tau in the regulation of presynaptic function.

Summary: Kibra is a synaptic scaffold protein regulating learning and memory. Alterations of Kibra-encoding gene WWC1 cause various neuronal disorders, including Alzheimer’s disease and Tourette syndrome. However, the molecular mechanism underlying Kibra’s function in neurons is poorly understood. Here we discover that Kibra, via its N-terminal WW12 tandem domains, binds to a postsynaptic density enriched protein, Dendrin, with a nanomolar dissociation constant. On the basis of the structure of Kibra WW12 in complex with Dendrin PY motifs, we developed a potent peptide inhibitor capable of specifically blocking the binding between Kibra and Dendrin in neurons. Systematic administration of the inhibitory peptide attenuated excitatory synaptic transmission, completely blocked long-term potentiation induction, and impaired spatial learning and memory. A Kibra mutation found in Tourette syndrome patients causes defects in binding to Dendrin. Thus, Kibra can modulate spatial learning and memory via binding to Dendrin. : Ji et al. report that the memory-related molecule Kibra, via its WW tandem domains, specifically binds to the synaptic protein Dendrin with a low-nanomolar dissociation constant to modulate spatial learning and memory. Keywords: Kibra, Dendrin, WW domains, tandem repeats, scaffold protein, synaptic complex, synaptic transmission, learning and memory, psychiatric disorder, Tourette syndrome

Impairments of dendritic trees and spines have been found in many neurodegenerative diseases, including Alzheimer's disease (AD), in which the deficits of melatonin signal pathway were reported. Melatonin receptor 2 (MT2) is widely expressed in the hippocampus and mediates the biological functions of melatonin. It is known that melatonin application is protective to dendritic abnormalities in AD. However, whether MT2 is involved in the neuroprotection and the underlying mechanisms are not clear. Here, we first found that MT2 is dramatically reduced in the dendritic compartment upon the insult of oligomer Aβ. MT2 activation prevented the Aβ‐induced disruption of dendritic complexity and spine. Importantly, activation of MT2 decreased cAMP, which in turn inactivated transcriptional factor CCAAT/enhancer‐binding protein α(C/EBPα) to suppress miR‐125b expression and elevate the expression of its target, GluN2A. In addition, miR‐125b mimics fully blocked the protective effects of MT2 activation on dendritic trees and spines. Finally, injection of a lentivirus containing a miR‐125b sponge into the hippocampus of APP/PS1 mice effectively rescued the dendritic abnormalities and learning/memory impairments. Our data demonstrated that the cAMP‐C/EBPα/miR‐125b/GluN2A signaling pathway is important to the neuroprotective effects of MT2 activation in Aβ‐induced dendritic injuries and learning/memory disorders, providing a novel therapeutic target for the treatment of AD synaptopathy.

The hippocampus is divided into dorsal and ventral zones along its principal axis. The dorsal hippocampus is critical for learning and memory, yet the basic function of the ventral hippocampus remains elusive. Here we genetically manipulate a subset of excitatory neurons expressing the serotonin receptor 2c (Htr2c) in the ventral hippocampus. Genetically modified virus tracing reveals that these Htr2c cells establish monosynaptic excitatory connections with newly identified neurons in the Edinger-Westphal nucleus (EW), which directly innervate the medial prefrontal cortex. Inactivation of Htr2c cells impairs behavioral performance in a visual-detection task that demands attention, without affecting novel-object recognition, learning, or memory. This attention deficit was recapitulated by inhibition of EW cells and rescued by activation of EW cells or synaptic projections from Htr2c cells onto EW cells. This study uncovers a synaptic pathway for control of attention.

The two estrogen receptors (ERs), ERα and ERβ, mediate the diverse biological functions of estradiol. Opposite effects of ERα and ERβ have been found in estrogen-induced cancer cell proliferation and differentiation as well as in memory-related tasks. However, whether these opposite effects are implicated in the pathogenesis of Alzheimer’s disease (AD) remains unclear. Here, we find that ERα and ERβ play contrasting roles in regulating tau phosphorylation, which is a pathological hallmark of AD. ERα increases the expression of miR-218 to suppress the protein levels of its specific target, protein tyrosine phosphatase α (PTPα). The downregulation of PTPα results in the abnormal tyrosine hyperphosphorylation of glycogen synthase kinase-3β (resulting in activation) and protein phosphatase 2A (resulting in inactivation), the major tau kinase and phosphatase. Suppressing the increased expression of miR-218 inhibits the ERα-induced tau hyperphosphorylation as well as the PTPα decline. In contrast, ERβ inhibits tau phosphorylation by limiting miR-218 levels and restoring the miR-218 levels antagonized the attenuation of tau phosphorylation by ERβ. These data reveal for the first time opposing roles for ERα and ERβ in AD pathogenesis and suggest potential therapeutic targets for AD.

Cognition in all mammals including human beings declines during aging. The cellular events responsible for this decay involve a reduction of neurogenesis in the dentate gyrus. Here, we show that treatment with a nature product from a traditional Chinese medicine, namely salidroside restores the capacity of the dentate gyrus to generate new neurons and intercepts learning and memory decays in mice during aging. We uncover that new neurons in aging mice have functional features of an adult granule neuron by forming excitatory synapses with their putative targeting neurons. Genetic inhibition of synaptic transmission from new neurons abolishes the therapeutic effects of salidroside in behavioral tests. We also identify that salidroside targets CREB transcription for the survival of new neurons in the dentate gyrus of old mice. Thus, salidroside is therapeutically effective against learning and memory decays via stimulation of CREB-dependent functional neurogenesis in aging.

Cholinergic system is very important for many higher brain functions, including learning and memory. Cholinergic neurons, especially those in the basal forebrain, are specifically susceptible in some neurodegenerative diseases, such as in Alzheimer’s disease (AD). Here, we studied the cholinergic system lesion effects of five familial AD mutations in 5XFAD mice, a transgenic mouse model of AD. Although the cholinergic system has been studied in this mouse model, the cholinergic deficits in AD mice have never been systematically mapped in a whole-brain three-dimensional (3D) reconstruction. Using the 3D reconstruction technology combined with immunohistochemistry (3D-IHC) and design-based stereology, we comprehensively compared the differences of the cholinergic neurons and fibers between the 5XFAD mice and C57BL/6 control mice at different age. Here, we found that the lesion of cholinergic fibers occurred earlier than the cholinergic neuron loss in 5XFAD mice. The cholinergic fiber lesions in the AD mice started sequentially in amygdala, cortex, hippocampus, and then basal forebrain. However, the basal forebrain was the first brain region observed with cholinergic neuron loss at the age of 9 months in 5XFAD mice, whereas such phenomenon first occurred at the age of 15 months in C57BL/6 control mice. Moreover, using 3D reconstruction to compare the lesion of cholinergic system of aged 5XFAD and C57BL/6 control mice, it is intuitive to notice the pathologic regions and severity of lesion. Therefore, the 3D-IHC provides detailed overview of the cholinergic neurons in the whole mouse brain, which will contribute to the study of the developing and pathologic mouse brain.

The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer’s disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scaling of HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD. Electronic supplementary material The online version of this article (doi:10.1186/s40478-016-0398-0) contains supplementary material, which is available to authorized users.

Necrosis and apoptosis are two distinct types of mechanisms that mediate ischemic injury. But a signaling point of convergence between them has yet to be identified. Here, we show that activated death-associated protein kinase 1 (DAPK1), phosphorylates p53 at serine-23 (pS23) via a direct binding of DAPK1 death domain (DAPK1DD) to the DNA binding motif of p53 (p53DM). We uncover that thepS23acts as a functional version of p53 and mediates necrotic and apoptotic neuronal death; in the nucleus,pS23induces the expression of proapoptotic genes, such asBax, whereas in the mitochondrial matrix,pS23triggers necrosis via interaction with cyclophilin D (CypD) in cultured cortical neurons from mice. Deletion of DAPK1DD (DAPK1DDΔ) or application of Tat-p53DM that interrupts DAPK1–p53 interaction blocks these dual pathways ofpS23actions in mouse cortical neurons. Thus, the DAPK1–p53 interaction is a signaling point of convergence of necrotic and apoptotic pathways and is a desirable target for the treatment of ischemic insults.

The over-production of β-amyloid (Aβ) has been strongly correlated to neuronal dysfunction and altered synaptic plasticity in Alzheimer’s disease (AD). Accordingly, it has been proposed that disrupted synaptic transmission and neuronal network instability underlie memory failure that is evident in the early phases of AD. Homeostatic synaptic plasticity (HSP) serves to restrain neuronal activity within a physiological range. Therefore a disruption of this mechanism may lead to destabilization in synaptic and neural circuit function. Here, we report that during HSP by neuronal activity deprivation, application of Aβ results in an aberrant over-response of the up-regulation of AMPA receptor (AMPAR)-mediated synaptic currents and cell-surface AMPAR expression. In the visual cortex, in vivo HSP induced by visual deprivation shows a similar over-response following an Aβ local injection. Aβ increases the expression of GluA2-lacking, calcium permeable AMPARs (CP-AMPARs), which are required for the initiation, but not maintenance of HSP. Both GluA2-lacking and GluA2-containing AMPARs contribute to the Aβ-mediated over-scaling of HSP. We also find that Aβ induces the dissociation of HDAC1 from the miR124 transcription factor EVI1, leading to an up-regulation of miR124 expression and increased amount of CP-AMPARs. Thus, via aberrant stimulation of miR124 expression and biogenesis of CP-AMPARs, Aβ is able to induce an over response in HSP. This Aβ-mediated dysregulation in homeostatic plasticity may play an important role in the pathogenesis of altered neural function and memory deficits in the early stages of AD.

Clinical data have shown women are more susceptible to depression. This study was performed to identify differentially regulated proteins from hippocampus in chronic unpredicted mild stress (CUMS)-exposed male and female young rats. After 7 weeks of CUMS, depressed male (M-D) and female rats (F-D) and unstressed male (M-C) and female controls (F-C) were studied. By proteomics analysis, 74 differential proteins in F-C/M-C, 79 in F-D/M-D, 77 in F-D/F-C, and 32 in M-D/M-C were found. Further, the synapse-related proteins, cytoskeleton protein tau, and stress-related kinases in hippocampus were assayed by Western blotting. F-C rats were found to have lower levels of metabotropic glutamate receptor 1 (mGluR1) and mGluR2 and higher levels of N-methyl-D-aspartate receptor 2B (NR2B), synapsin1, total tau, and dephosphorylated tau than M-C rats. Both F-D and M-D rats had lower levels of glutamate transporter SLC1α2, mGluR1, and mGluR2, and higher levels of total tau and phosphorylated tau than their controls. Compared with their controls, M-D rats had lower NR1 and higher NR2B, and F-D rats had lower NR2A, NR2B, PSD95, and synapsin1. F-C rats had higher JNK and lower phosphorylation levels of ERK at Thr202/Thr204, JNK at Thr183/Thr185, and GSK-3β at Ser9 than M-C ones. Both M-D and F-D rats had decreased phosphorylation of ERK at Thr202/Thr204 and GSK-3β at Ser9, and increased JNK phosphorylation at Thr183/Thr185 compared with their controls. All these data illustrate the biochemical complexity behind the genders, and may also aid in the development of more accurate treatment strategies for depression.

Background Synaptic loss is an early pathological event in Alzheimer’s disease (AD), but its underlying molecular mechanisms remain largely unknown. Recently, microRNAs (miRNAs) have emerged as important modulators of synaptic function and memory. Methods We used miRNA array and quantitative polymerase chain reaction to examine the alteration of miRNAs in AD mice and patients as well as the Morris water maze to evaluate learning and memory in the mice. We also used adeno-associated virus or lentivirus to introduce tyrosine-protein phosphatase non-receptor type 1 (PTPN1) expression of silencing RNAs. Long-term potentiation and Golgi staining were used to evaluate the synaptic function and structure. We designed a peptide to interrupt miR-124/PTPN1 interaction. Results Here we report that neuronal miR-124 is dramatically increased in the hippocampus of Tg2576 mice, a recognized AD mouse model. Similar changes were observed in specific brain regions of affected AD individuals. We further identified PTPN1 as a direct target of miR-124. Overexpression of miR-124 or knockdown of PTPN1 recapitulated AD-like phenotypes in mice, including deficits in synaptic transmission and plasticity as well as memory by impairing the glutamate receptor 2 membrane insertion. Most importantly, rebuilding the miR-124/PTPN1 pathway by suppression of miR-124, overexpression of PTPN1, or application of a peptide that disrupts the miR-124/PTPN1 interaction could restore synaptic failure and memory deficits. Conclusions Taken together, these results identified the miR-124/PTPN1 pathway as a critical mediator of synaptic dysfunction and memory loss in AD, and the miR-124/PTPN1 pathway could be considered as a promising novel therapeutic target for AD patients.

Summary: Retroactive interference (RI) occurs when new incoming information impairs an existing memory, which is one of the primary sources of forgetting. Although long-term potentiation (LTP) reversal shows promise as the underlying neural correlate, the key molecules that control the sensitivity of memory circuits to RI are unknown, and the developmental trajectory of RI effects is unclear. Here we found that depotentiation in the hippocampal dentate gyrus (DG) depends on GluN2A-containing NMDA receptors (NMDARs). The susceptibility of LTP to disruption progressively increases with the rise in the GluN2A/GluN2B ratio during development. The vulnerability of hippocampus-dependent memory to interference from post-learning novelty exploration is subject to similar developmental regulation by NMDARs. Both GluN2A overexpression and GluN2B downregulation in the DG promote RI-induced forgetting. Altogether, our results suggest that a switch in GluN2 subunit predominance may confer age-related differences to depotentiation and underlie the developmental decline in memory resistance to RI. : Ge et al. report that the NMDA receptor GluN2A/GluN2B subunit ratio determines the sensitivity of strengthened neuronal connections to depotentiation. As the ratio rises during development, memories become more vulnerable to disruption by post-learning interference. These findings help to illuminate the mechanism by which forgetting rates may vary with age. Keywords: forgetting, retroactive interference, depotentiation, NMDA receptor

The entorhinal cortex (EC) is one of the most vulnerable brain regions that is attacked during the early stage of Alzheimer's disease (AD). Here, we report that the synaptic terminals of pyramidal neurons in the EC layer II (ECIIPN) directly innervate CA1 parvalbumin (PV) neurons (CA1PV) and are selectively degenerated in AD mice, which exhibit amyloid-β plaques similar to those observed in AD patients. A loss of ECIIPN-CA1PV synapses disables the excitatory and inhibitory balance in the CA1 circuit and impairs spatial learning and memory. Optogenetic activation of ECIIPN using a theta burst paradigm rescues ECIIPN-CA1PV synaptic defects and intercepts the decline in spatial learning and memory. These data reveal a novel mechanism of memory loss in AD mice via the selective degeneration of the ECIIPN-CA1PV pathway.

Alzheimer’s disease (AD) is a late-onset progressive neurodegenerative disorder that leads to cognitive, memory and behavioural impairments. Substantial evidence indicates that disrupted neuronal calcium homeostasis is an early event in AD that could mediate synaptic dysfunction and neuronal toxicity. Sodium calcium exchangers (NCXs) play important roles in regulating intracellular calcium, and accumulated data suggests that reduced NCX function, following aberrant proteolytic cleavage of these exchangers, may contribute to neurodegeneration. This review, characterizes the expression and activity of NCX as a prominent feature of AD brain, identifies the molecular mechanisms underlying the effects of NCX isoforms, and pinpoints the molecular determinants responsible for the effects of NCX. Our findings suggest that calpain mediates cleavage of NCX3 in AD brain and therefore that reduced NCX3 activity contributes to the sustained increases in intraneuronal calcium concentrations that are associated with caspase-12 activation and neuronal death in AD.

Chronic intake of nicotine can impair hippocampal plasticity, but the underlying mechanism is poorly understood. Here, we demonstrate that chronic nicotine administration in adult rats inactivates the cyclic AMP-response element binding protein (CREB), a transcription factor that regulates neurogenesis and other plasticity-related processes necessary for learning and memory. Consequently, we showed that impaired CREB signaling is associated with a significant decline in the production of new neurons in the dentate gyrus. Combining retrovirus labeling with gene expression approaches, we found that chronic nicotine administration reduces the number of adult-generated granule neurons by decreasing the survival of newborn cells but not the proliferation of progenitor cells. Additionally, we found that retroviral-mediated expression of a constitutively active CREB in the dentate gyrus rescues survival of newborn cells and reverses the nicotine-induced decline in the number of mature granule neurons. Prolonged nicotine exposure also compromises CREB activation and reduces the viability of progenitor cells in vitro, thereby suggesting that nicotine may exert its adverse effects directly on immature cells in vivo. Taken together, these data demonstrate that inhibition of CREB activation is responsible for the nicotine-induced impairment of hippocampal plasticity.

EPAC proteins are the guanine nucleotide exchange factors that act as the intracellular receptors for cyclic AMP. Two variants of EPAC genes including EPAC1 and EPAC2 are cloned and are widely expressed throughout the brain. But, their functions in the brain remain unknown. Here, we genetically delete EPAC1 (EPAC1(-/-)), EPAC2 (EPAC2(-/-)), or both EPAC1 and EPAC2 genes (EPAC(-/-)) in the forebrain of mice. We show that EPAC null mutation impairs long-term potentiation (LTP) and that this impairment is paralleled with the severe deficits in spatial learning and social interactions and is mediated in a direct manner by miR-124 transcription and Zif268 translation. Knockdown of miR-124 restores Zif268 and hence reverses all aspects of the EPAC(-/-) phenotypes, whereas expression of miR-124 or knockdown of Zif268 reproduces the effects of EPAC null mutation. Thus, EPAC proteins control miR-124 transcription in the brain for processing spatial learning and social interactions.

Glucose-stimulated insulin secretion (GSIS) from pancreatic β-cells is potentiated by cAMP-elevating agents, such as the incretin hormone glucagon-like peptide-1 (GLP-1), and cAMP exerts its insulin secretagogue action by activating both protein kinase A (PKA) and the cAMP-regulated guanine nucleotide exchange factor designated as Epac2. Although prior studies of mouse islets demonstrated that Epac2 acts via Rap1 GTPase to potentiate GSIS, it is not understood which downstream targets of Rap1 promote the exocytosis of insulin. Here, we measured insulin secretion stimulated by a cAMP analog that is a selective activator of Epac proteins in order to demonstrate that a Rap1-regulated phospholipase C-epsilon (PLC-ε) links Epac2 activation to the potentiation of GSIS. Our analysis demonstrates that the Epac activator 8-pCPT-2'-O-Me-cAMP-AM potentiates GSIS from the islets of wild-type (WT) mice, whereas it has a greatly reduced insulin secretagogue action in the islets of Epac2 (-/-) and PLC-ε (-/-) knockout (KO) mice. Importantly, the insulin secretagogue action of 8-pCPT-2'-O-Me-cAMP-AM in WT mouse islets cannot be explained by an unexpected action of this cAMP analog to activate PKA, as verified through the use of a FRET-based A-kinase activity reporter (AKAR3) that reports PKA activation. Since the KO of PLC-ε disrupts the ability of 8-pCPT-2'-O-Me-cAMP-AM to potentiate GSIS, while also disrupting its ability to stimulate an increase of β-cell [Ca2+]i, the available evidence indicates that it is a Rap1-regulated PLC-ε that links Epac2 activation to Ca2+-dependent exocytosis of insulin.

Synaptic mechanism in Alzheimer’s disease: a selective degeneration of an excitatory synaptic pathway in the CA1 hippocampus that controls spatial learning and memory in Alzheimer’s disease

SummaryN-methyl-D-aspartate (NMDA) receptors constitute a major subtype of glutamate receptors at extrasynaptic sites that link multiple intracellular catabolic processes responsible for irreversible neuronal death. Here, we report that cerebral ischemia recruits death-associated protein kinase 1 (DAPK1) into the NMDA receptor NR2B protein complex in the cortex of adult mice. DAPK1 directly binds with the NMDA receptor NR2B C-terminal tail consisting of amino acid 1292-1304 (NR2BCT). A constitutively active DAPK1 phosphorylates NR2B subunit at Ser-1303 and in turn enhances the NR1/NR2B receptor channel conductance. Genetic deletion of DAPK1 or administration of NR2BCT that uncouples an activated DAPK1 from an NMDA receptor NR2B subunit in vivo in mice blocks injurious Ca2+ influx through NMDA receptor channels at extrasynaptic sites and protects neurons against cerebral ischemic insults. Thus, DAPK1 physically and functionally interacts with the NMDA receptor NR2B subunit at extrasynaptic sites and this interaction acts as a central mediator for stroke damage.

Summary Aberrant cell-cycle activity and DNA damage are emerging as important pathological components in various neurodegenerative conditions. However, their underlying mechanisms are poorly understood. Here, we show that deregulation of histone deacetylase 1 (HDAC1) activity by p25/Cdk5 induces aberrant cell-cycle activity and double-strand DNA breaks leading to neurotoxicity. In a transgenic model for neurodegeneration, p25/Cdk5 activity elicited cell-cycle activity and double-strand DNA breaks that preceded neuronal death. Inhibition of HDAC1 activity by p25/Cdk5 was identified as an underlying mechanism for these events, and HDAC1 gain of function provided potent protection against DNA damage and neurotoxicity in cultured neurons and an in vivo model for ischemia. Our findings outline a pathological signaling pathway illustrating the importance of maintaining HDAC1 activity in the adult neuron. This pathway constitutes a molecular link between aberrant cell-cycle activity and DNA damage and is a potential target for therapeutics against diseases and conditions involving neuronal death.

Neurogenesis continues throughout adulthood in the central nervous system in mammals. Cerebral ischemia induces neurogenesis in the subventricular zone and dentate gyrus. New neurons migrate to the granule cell layer of dentate gyrus or to the damaged CA1 region and striatum, where they differentiate into mature neurons and re-establish connections. Ischemic insults also promote axonal sprouting in ischemic penumbra. Neurogenesis and axonal sprouting may contribute to functional recovery after cerebral ischemia.

Neurogenesis in the adult mammalian hippocampus may contribute to repairing the brain after injury. The signals that regulate neurogenesis in the dentate gyrus following ischemic stroke insult are not well known. We have previously reported that inducible nitric oxide synthase (iNOS) expression is necessary for ischemia-stimulated neurogenesis in the adult dentate gyrus. Here, we show that mice subjected to 90 min of middle cerebral artery occlusion (MCAO) significantly increased the number of new neurons and up-regulated iNOS expression in the dentate gyrus. Blockade of the L-type voltage-gated Ca(2+) channel (L-VGCC) prevented neurogenesis in the dentate gyrus and subventricular zone (SVZ), and down-regulated iNOS expression in the dentate gyrus after cerebral ischemia. This study suggests that Ca(2+) influx through L-VGCC is involved in ischemia-induced neurogenesis by up-regulating iNOS expression.