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Alzheimer's disease (AD) is an incurable, age-related and progressive neurodegenerative disease characterized by cognitive impairments. Deficits in synaptic plasticity were reported in various models of AD-like pathology and are considered as an early contributing factor of cognitive impairment. However, the majority of previous studies were focused on overt, symptomatic stages of pathology and assessed long-term potentiation (LTP), whereas long-term depression (LTD) was much less investigated and the precise nature of its involvement remains poorly defined. To better understand the earliest synaptic dysfunctions along the pre-symptomatic stage of AD-like pathology, we performed a detailed analysis of underlying mechanisms and quantified basal synaptic activity, presynaptic release probability, and synaptic plasticity such as post-tetanic potentiation (PTP), as well as LTP and LTD. These parameters were studied in APPPS1 mouse model at two time points (early- and mid-) along the pre-symptomatic stage, which were compared with alterations monitored at two later time-points, i.e. the onset of cognitive deficits and the overt stage of full-blown pathology. Because sex is known to be an instrumental biological parameter in AD pathophysiology, all alterations were assessed in both males and females. Our data show that, as compared to wild-type (WT) littermates, initial neuronal hyperexcitability, seen at early pre-symptomatic stage shifts subsequently towards hypoexcitability at mid-pre-symptomatic stage and remains impaired at advanced stages. The pre-symptomatic changes also involve increased synaptic plasticity as assessed by paired-pulse facilitation (PPF), which returns to basal level at the onset of pathology and remains stable afterwards. Synaptic plasticity is impaired by mid-pre-symptomatic stage and manifests as lowered LTP and absence of LTD induction, the latter being reported here for the first time. Observed LTP and LTD impairments both persist in older APPPS1 mice. Remarkably, none of the observed differences was gender-dependent. Altogether, our data evidence that major impairments in basal synaptic efficacy and plasticity are detectable already during mid-pre-symptomatic stage of AD-like pathogenesis and likely involve hyperexcitability as the underlying mechanism. Our study also uncovers synaptic alterations that may become critical read-outs for testing the efficiency of novel, pre-symptomatic stage-targeted therapies for AD. • Alzheimer's Disease (AD) displays a long pre-symptomatic stage (PSS). • AD is still incurable since treated late and targeting PSS may be more efficient. • PSS is impossible to assess in human and requires models to identify early targets. • Using a mouse AD model, we identified a novel marker of PSS synaptic dysfunction. • This marker can serve as a read-out for testing efficacy of PSS-targeted therapies. [ABSTRACT FROM AUTHOR]

Objective: d-Serine is a crucial endogenous co-agonist of N-methyl-d-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (BDNF) system, which plays an essential role in modulating synaptic plasticity. The current study aimed to systematically evaluate the role and mechanisms of d-serine in depressive behavior in nucleus accumbens (NAc). Methods: d-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured using high-performance liquid chromatography (HPLC). The antidepressant-like effects of d-serine were identified using forced swim test (FST) and tail suspension test (TST) in control mice and then assessed in CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and d-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant-like mechanism of d-serine. Moreover, d-serine effects on synaptic plasticity in NAc were investigated using electrophysiological methods. Results: d-Serine concentration was decreased in depression susceptible mice in NAc. d-Serine injections into NAc exhibited antidepressant-like effects in FST and TST without affecting the locomotor activity of mice. d-Serine was also effective in CSDS model of depression. Moreover, d-serine down-regulated the BDNF signaling pathway in NAc during CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of d-serine. We also found that d-serine was essential for NMDARs-dependent long-term depression (LTD). Conclusion: d-Serine exerts antidepressant-like effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc. [ABSTRACT FROM AUTHOR]

Human mutations of the Na+-activated K+ channel Slack (KCNT1) are associated with epilepsy and intellectual disability. Accordingly, Slack knockout mice (Slack−/−) exhibit cognitive flexibility deficits in distinct behavioral tasks. So far, however, the underlying causes as well as the role of Slack in hippocampus-dependent memory functions remain enigmatic. We now report that infant (P6–P14) Slack−/− lack both hippocampal LTD and LTP, likely due to impaired NMDA receptor (NMDAR) signaling. Postsynaptic GluN2B levels are reduced in infant Slack−/−, evidenced by lower amplitudes of NMDAR-meditated excitatory postsynaptic potentials. Low GluN2B affected NMDAR-mediated Ca2+-influx, rendering cultured hippocampal Slack−/−neurons highly insensitive to the GluN2B-specific inhibitor Ro 25-6981. Furthermore, dephosphorylation of the AMPA receptor (AMPAR) subunit GluA1 at S845, which is involved in AMPAR endocytosis during homeostatic and neuromodulator-regulated plasticity, is reduced after chemical LTD (cLTD) in infant Slack−/−. We additionally detect a lack of mGluR-induced LTD in infant Slack−/−, possibly caused by upregulation of the recycling endosome-associated small GTPase Rab4 which might accelerate AMPAR recycling from early endosomes. Interestingly, LTP and mGluR LTD, but not LTD and S845 dephosphorylation after cLTD are restored in adult Slack−/−. This together with normalized expression levels of GluN2B and Rab4 hints to developmental "restoration" of LTP expression despite Slack ablation, whereas in infant and adult brain, NMDAR-dependent LTD induction depends on this channel. Based on the present findings, NMDAR and vesicular transport might represent novel targets for the therapy of intellectual disability associated with Slack mutations. Consequently, careful modulation of hippocampal Slack activity should also improve learning abilities. [ABSTRACT FROM AUTHOR]

Objective: d-Serine is a crucial endogenous co-agonist of N-methyl-d-aspartate receptors (NMDARs) in the central nervous system and can affect the function of the brain derived neurotrophic factor (BDNF) system, which plays an essential role in modulating synaptic plasticity. The current study aimed to systematically evaluate the role and mechanisms of d-serine in depressive behavior in nucleus accumbens (NAc). Methods: d-Serine concentration in the chronic social defeat stress (CSDS) model in NAc was measured using high-performance liquid chromatography (HPLC). The antidepressant-like effects of d-serine were identified using forced swim test (FST) and tail suspension test (TST) in control mice and then assessed in CSDS model. We applied social interaction and sucrose preference tests to identify the susceptibility of CSDS model. Western blotting was further performed to assess the changes of BDNF signaling cascade in NAc after CSDS and d-serine treatment. The BDNF signaling inhibitor (K252a) was also used to clarify the antidepressant-like mechanism of d-serine. Moreover, d-serine effects on synaptic plasticity in NAc were investigated using electrophysiological methods. Results: d-Serine concentration was decreased in depression susceptible mice in NAc. d-Serine injections into NAc exhibited antidepressant-like effects in FST and TST without affecting the locomotor activity of mice. d-Serine was also effective in CSDS model of depression. Moreover, d-serine down-regulated the BDNF signaling pathway in NAc during CSDS procedure. Furthermore, BDNF signaling inhibitor (K252a) enhanced the antidepressant effects of d-serine. We also found that d-serine was essential for NMDARs-dependent long-term depression (LTD). Conclusion: d-Serine exerts antidepressant-like effects in mice mediated through restraining the BDNF signaling pathway and regulating synaptic plasticity in NAc. [ABSTRACT FROM AUTHOR]

In social animals, the behavioral and hormonal responses to stress can be transmitted from one individual to another through a social transmission process, and, conversely, social support ameliorates stress responses, a phenomenon referred to as social buffering. Metaplasticity represents activity-dependent synaptic changes that modulate the ability to elicit subsequent synaptic plasticity. Authentic stress can induce hippocampal metaplasticity, but whether transmitted stress has the same ability remains unknown. Here, using an acute restraint-tailshock stress paradigm, we report that both authentic and transmitted stress in adult male mice trigger metaplastic facilitation of long-term depression (LTD) induction at hippocampal CA1 synapses. Using LTD as a readout of persistent synaptic consequences of stress, our findings demonstrate that, in a male-male dyad, stress transmission happens in nearly half of naive partners and stress buffering occurs in approximately half of male stressed mice that closely interact with naive partners. By using a social-confrontation tube test to assess the dominant-subordinate relationship in a male-male dyad, we found that stressed subordinate mice are not buffered by naive dominant partners and that stress transmission is exhibited in; 60% of dominant naive partners. Furthermore, the appearance of stress transmission correlates with more time spent in sniffing the anogenital area of stressed mice, and the appearance of stress buffering correlates with more time engaged in allogrooming from naive partners. Chemical ablation of the olfactory epithelium with dichlobenil or physical separation between social contacts diminishes stress transmission. Together, our data demonstrate that transmitted stress can elicit metaplastic facilitation of LTD induction as authentic stress. [ABSTRACT FROM AUTHOR]

Transcranial magnetic stimulation (TMS) is a non-invasive, non-pharmacological technique that is able to modulate cortical activity beyond the stimulation period. The residual aftereffects are akin to the plasticity mechanism of the brain and suggest the potential use of TMS for therapy. For years, TMS has been shown to transiently improve symptoms of neuropsychiatric disorders, but the underlying neural correlates remain elusive. Recently, there is evidence that altered connectivity of brain network dynamics is the mechanism underlying symptoms of various neuropsychiatric illnesses. By combining TMS and electroencephalography (EEG), the functional connectivity patterns among brain regions, and the causal link between function or behaviour and a specific brain region can be determined. Nonetheless, the brain network connectivity are highly complex and involve the dynamics interplay among multitude of brain regions. In this review article, we present previous TMS-EEG co-registration studies, which explore the functional connectivity patterns of human cerebral cortex. We argue the possibilities of neural correlates of long-term potentiation/ depression (LTP-/LTD)-like mechanisms of synaptic plasticity that drive the TMS aftereffects as shown by the dissociation between EEG and motor evoked potentials (MEP) cortical output. Here, we also explore alternative explanations that drive the EEG oscillatory modulations post TMS. The precise knowledge of the neurophysiological mechanisms underlying TMS will help characterise disturbances in oscillatory patterns, and the altered functional connectivity in neuropsychiatric illnesses. [ABSTRACT FROM AUTHOR]

Highlights: [•] Allantoin enhanced cognitive function in the passive avoidance task. [•] Allantoin activated the phosphorylation of PI3K-Akt-GSK-3β pathway. [•] Allantoin increased neurogenesis in the hippocampal dentate gyrus region. [Copyright &y& Elsevier]

Exposure to the group I metabotropic glutamate receptor (mGluR) agonist dihydroxy phenylglycine (DHPG) induces epileptiform activity in the CA3 region of the hippocampus that persists following washout of DHPG. DHPG also can cause long-term depression of synaptic transmission, and at some synapses this may be mediated by endocannabinoids. We evaluated whether the selective cannabinoid type 1 (CB1) receptor antagonists SR 141716 or AM 251 could modify induction of epileptiform activity produced by DHPG exposure. The induction of epileptiform activity by DHPG exposure was significantly reduced by CB1 receptor antagonists, SR 141716 or AM 251. Minimal effects on epileptiform activity were noted once the activity had been induced. In control slices, exposure to DHPG for 30 min produced long-term depression (LTD) of synaptic transmission, on average about a 70% reduction in slope of the field excitatory postsynaptic potential (EPSP). When slices were exposed to both DHPG and SR 141716 (3 μm), LTD did not occur and the population EPSP remained at control values or greater. These results suggest that CB1 receptors mediate some of DHPG effects that result in persistent epileptiform activity, and antagonism of CB1 receptors has antiepileptogenic properties. Paradoxically DHPG also caused LTD of excitatory synaptic transmission in the CA3 region and CB1 receptor antagonism prevents the depression. We hypothesize that the ictal activity induced by DHPG requires depression of synaptic strength and CB1 receptor antagonism prevents this depression and the induction of ictal activity. [ABSTRACT FROM AUTHOR]

One niche of experimental biology that has experienced considerable progress is the neurobiology of learning and memory. A key contributor to such progress has been the widespread use of transgenic and 'knockout' mice to elucidate the mechanisms of identifiable phenotypes of learning and memory. Inbred mouse strains are needed to generate genetically modified mice. However, genetic variations between inbred strains can confound the interpretation of cellular neurophysiological phenotypes of mutant mice. It is known that altered physiological strength of synaptic transmission ('synaptic plasticity') can modify and regulate learning and memory. Characterization of the synaptic phenotypes of inbred mouse strains is needed to identify the most appropriate strains to use for generating mutant mouse models of memory function. More importantly, comparative electrophysiological analyses of inbred mice per se can also shed light on which forms of synaptic plasticity underlie particular types of learning and memory. Many such analyses have focused on synaptic plasticity in the hippocampus because of the critical roles of this brain structure in the formation and consolidation of long-term memories. Comparative electrophysiological data obtained from several inbred mouse strains are reviewed here to highlight the following key notions: (1) synaptic plasticity is influenced by the genetic backgrounds of inbred mice; (2) the plasticity of hippocampal synapses in inbred mice is `tuned' to particular temporal patterns of activity; (3) long-term potentiation, but not long-term depression, is a cellular correlate of behavioural memory performance in some strains; (4) synaptic phenotyping of inbred mouse strains can identify cellular models of memory impairment that can be used to elucidate mechanisms that may cause specific memory deficits. [ABSTRACT FROM AUTHOR]

Aluminium (Al), has the potential to be neurotoxic in humans and animals, and is present in many manufactured foods and medicines and is also added to drinking water for purification purposes. Our previous study demonstrated that chronic Al exposure induced deficits of both long-term potentiation (LTP) and long-term depression (LTD) of excitatory postsynaptic potential (EPSP) and population spike (PS) in rat dentate gyrus (DG) of hippocampus in vivo (Wang et al., 2001). The purpose of the present study was to investigate whether the Al-induced impairment of synaptic plasticity could be reversed by dietary supplementation with vitamin E (Vit E; α-tocopherol). Neonatal Wistar rats were exposed to Al from parturition throughout life by drinking 0.3% aluminium chloride (AlCl3) solution or a diet supplemented with Vit E at 500 μg/g/day with 0.3% AlCl3. The input/output (I/O) function, EPSP and PS were measured in DG area of adult rats (80–100 days of age) in response to stimulation applied to the lateral perforant path. The results showed that: (1) chronic Al exposure reduced the amplitudes of both EPSP LTP (control: 130.4±3%, n=7; Al-exposed: 110±2%, n=9, P<0.001) and PS LTP (control: 241±19%, n=7; Al-exposed: 130±7%, n=9, P<0.001) significantly. Vit E had no significant effects on the Al-induced deficits of EPSP LTP (Al-exposed: 110±2%, n=9; Al-exposed+Vit E: 112±2%, n=8, P>0.05) and PS LTP (Al-exposed: 130±7%, n=9; Al-exposed+Vit E: 129±4%, n=8; P>0.05); (2) the amplitudes of EPSP LTD (control: 84±4%, n=7; Al-exposed: 92±7%, n=9, P<0.01) and PS LTD (control: 81±4%, n=7; Al-exposed: 98±5%, n=9, P<0.001) were also decreased by Al treatment. The impaired EPSP LTD (Al-exposed: 92±7%, n=9; Al-exposed+Vit E: 93±4%, n=8, P>0.05) and PS LTD (Al-exposed: 98±5%, n=9; Al-exposed+Vit E: 94±6%, n=8, P>0.05) were also not significantly affected by Vit E treatment. It was suggested that dietary supplementation with Vit E did not reverse the impairment of synaptic plasticity induced by Al in DG in vivo. [ABSTRACT FROM AUTHOR]

Long-term changes in synaptic transmission in the central nervous system, such as long-term potentiation and long-term depression (LTD), are believed to underlie learning and memory in vivo. Despite intensive research, the precise molecular mechanisms underlying these phenomena have remained unclear. LTD is most commonly caused by the endocytosis of postsynaptic AMPA-type glutamate receptors, triggered by activity-induced serine phosphorylation of the GluA2 subunit. Interestingly, cerebellar LTD, which occurs at synapses between parallel fibers (PFs; axons of granule cells) and Purkinje cells, is unique in requiring an additional type of glutamate receptor, the d2 receptor (GluD2). Cbln1 was recently identified as a GluD2 ligand that regulates PF synapse formation and maintenance. However, how GluD2 induces downstream signaling in Purkinje cells to regulate LTD induction is unknown. We here present evidence that GluD2 reduces the tyrosine phosphorylation level of the GluA2 subunit via PTPMEG, a protein tyrosine phosphatase that binds to GluD2›s C-terminus. We also found that the serine phosphorylation of GluA2, a crucial step for AMPA-receptor endocytosis, requires prior tyrosine dephosphorylation. Thus, GluD2 may serve as a gatekeeper for LTD induction by coordinating interactions between GluA2›s 2 phosphorylation sites. [ABSTRACT FROM AUTHOR]

In this paper, we propose a complex neuro-memristive synapse that exhibits the physiological acts of synaptic potentiation and depression of the human-brain. Specifically, the proposed neuromorphic synapse efficiently imitates the synaptic plasticity, especially long-term potentiation (LTP) and depression (LTD), and short-term facilitation (STF) and depression (STD), phenomena of a biological synapse. Similar to biological synapse, the short- or long-term potentiation (STF and LTP) or depression (STD or LTD) of the memristive synapse are distinguished on the basis of time or repetition of input cycles. The proposed synapse is also designed to exhibit the effect of reuptake and neurotransmitters diffusion processes of a bio-synapse. In addition, it exhibits the distinct bio-realistic attributes, i.e., strong stimulation, exponentially decaying conductance trace of synapse, and voltage dependent synaptic responses, of a neuron. The neuro-memristive synapse is designed in SPICE and its bio-realistic functionalities are demonstrated via various simulations. [ABSTRACT FROM AUTHOR]

Hexanucleotide repeat expansion of C9ORF72 is the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia. Synergies between loss of C9ORF72 functions and gain of toxicities from the repeat expansions contribute to C9ORF72-mediated pathogenesis. However, how loss of C9orf72 impacts neuronal and synaptic functions remains undetermined. Here, we showed that long-term potentiation at the dentate granule cells and long-term depression at the Schaffer collateral/commissural synapses at the area CA1 were reduced in the hippocampus of C9orf72 knockout mice. Using unbiased transcriptomic analysis, we identified that Klotho, a longevity gene, was selectively dysregulated in an age-dependent manner. Specifically, Klotho protein expression in the hippocampus of C9orf72 knockout mice was incorrectly enriched in the dendritic regions of CA1 with concomitant reduction in granule cell layer of dentate gyrus at 3-month of age followed by an accelerating decline during aging. Furthermore, adult hippocampal neurogenesis was reduced in C9orf72 knockout mice. Taken together, our data suggest that C9ORF72 is required for synaptic plasticity and adult neurogenesis in the hippocampus and Klotho deregulations may be part of C9ORF72-mediated toxicity. [ABSTRACT FROM AUTHOR]