Expression Of Long-term Potentiation Research Articles

Postnatal hypofunction of N-methyl-D-aspartate receptors alters perforant path synaptic plasticity and filtering and impairs dentate gyrus-mediated spatial discrimination.

Transient hypofunction of the NMDA receptor represents a convergence point for the onset and further development of psychiatric disorders, including schizophrenia. Although the cumulative evidence indicates dysregulation of the hippocampal formation in schizophrenia, the integrity of the synaptic transmission and plasticity conveyed by the somatosensorial inputs to the dentate gyrus, the perforant pathway synapses, have barely been explored in this pathological condition. We identified a series of synaptic alterations of the lateral and medial perforant paths in animals postnatally treated with the NMDA antagonist MK-801. This dysregulation suggests decreased cognitive performance, for which the dentate gyrus is critical. We identified alterations in the synaptic properties of the lateral and medial perforant paths to the dentate gyrus synapses in slices from MK-801-treated animals. Altered glutamate release and decreased synaptic strength precede an impairment in the induction and expression of long-term potentiation (LTP) and CB1 receptor-mediated long-term depression (LTD). Remarkably, by inhibiting the degradation of 2-arachidonoylglycerol (2-AG), an endogenous ligand of the CB1 receptor, we restored the LTD in animals treated with MK-801. Additionally, we showed for the first time, that spatial discrimination, a cognitive task that requires dentate gyrus integrity, is impaired in animals exposed to transient hypofunction of NMDA receptors. Dysregulation of glutamatergic transmission and synaptic plasticity from the entorhinal cortex to the dentate gyrus has been demonstrated, which may explain the cellular dysregulations underlying the altered cognitive processing in the dentate gyrus associated with schizophrenia.

Cdc42 activation is necessary for heterosynaptic cooperation and competition

Synapses change their weights in response to neuronal activity and in turn, neuronal networks alter their response properties and ultimately allow the brain to store information as memories. As for memories, not all events are maintained over time. Maintenance of synaptic plasticity depends on the interplay between functional changes at synapses and the synthesis of plasticity-related proteins that are involved in stabilizing the initial functional changes. Different forms of synaptic plasticity coexist in time and across the neuronal dendritic area. Thus, homosynaptic plasticity refers to activity-dependent synaptic modifications that are input-specific, whereas heterosynaptic plasticity relates to changes in non-activated synapses. Heterosynaptic forms of plasticity, such as synaptic cooperation and competition allow neurons to integrate events that occur separated by relatively large time windows, up to one hour. Here, we show that activation of Cdc42, a Rho GTPase that regulates actin cytoskeleton dynamics, is necessary for the maintenance of long-term potentiation (LTP) in a time-dependent manner. Inhibiting Cdc42 activation does not alter the time-course of LTP induction and its initial expression but blocks its late maintenance. We show that Cdc42 activation is involved in the phosphorylation of cofilin, a protein involved in modulating actin filaments and that weak and strong synaptic activation leads to similar levels on cofilin phosphorylation, despite different levels of LTP expression. We show that Cdc42 activation is required for synapses to interact by cooperation or competition, supporting the hypothesis that modulation of the actin cytoskeleton provides an activity-dependent and time-restricted permissive state of synapses allowing synaptic plasticity to occur. We found that under competition, the sequence in which synapses are activated determines the degree of LTP destabilization, demonstrating that competition is an active destabilization process. Taken together, we show that modulation of actin cytoskeleton by Cdc42 activation is necessary for the expression of homosynaptic and heterosynaptic forms of plasticity. Determining the temporal and spatial rules that determine whether synapses cooperate or compete will allow us to understand how memories are associated.

Orexin and cannabinoid systems modulate long-term potentiation of the hippocampus CA1 area in anesthetized rats.

Long-term potentiation (LTP) is a kind of synaptic plasticity and has a key role in learning and memory. Endocannabinoids and orexins are the endogenous systems that can modulate synaptic plasticity. Given that new studies have shown an interaction between cannabinoid and orexin systems in the brain, we decided to examine this interaction between the two systems on LTP induction in rat's hippocampus. Twenty-eight male Wistar rats were used for evaluating the effects of co-administrating of cannabinoid-1 receptor (CB1R) antagonist (AM251) and orexin-2 receptor (OX2R) antagonist (TCS OX2 29) on the induction of LTP in the Schaffer collateral-CA1 synapses of rat hippocampus. The drugs were microinjected into the CA1 area of rat hippocampus 30 min before inducing of LTP. Results showed that sole administration of the antagonists inhibited LTP, with respect to the control group. Also, co-administrating of them reduced LTP as compared to the control group, but not significantly more than that when the antagonists were solely microinjected into the CA1. Nonetheless, the inhibitory effect of concurrent administration of the antagonists on LTP lasted until the end of the recording. These results propose that endogenous cannabinoids and orexins play a role in the expression of LTP, at least by CA1-CB1Rs and CA1-OX2Rs, respectively. Finally, there is no interaction between CB1R and OX2R on the induction of LTP in the Schaffer collateral-CA1 synapses; therefore, these two systems possibly act through common signaling pathways in the hippocampus's CA1 region.

FC1: Effect of Transcranial Direct Current Stimulation (tDCS) on Left Dorsolateral Prefrontal Cortex (DLPFC) in Dementia with Lewy Bodies (DLB)

Introduction:tDCS application to the DLPFC is associated with the improvements of executive function, memory enhancement, language, processing speed, global cognitive symptoms and apathy over time after treatment. DLB is the second most common form of degenerative dementia. There is no FDA-approved medications that can slow, stop or improve the progression of cognitive declines in DLB. Identifying effective treatments is a critical issue for DLB. In neuropathology, extracelluar α-syn oligomers interfere with the expression of long-term potentiation(LTP), and influence memory and learning. tDCS has been proposed to affect long-term synaptic plasticity through LTP and long-term depression, thereby improving cognitive ability. So far, only two studies have evaluated the effect of tDCS in DLB. In this pilot study, we investigate the effect of tDCS on left DLPFC in DLB.Method:Fourteen DLB aged 55-90 years (mean age 76.4, with 4 males and 10 females) were included in a double-blind, randomized, sham-controlled cross over design study. DLB diagnostics is according to DSM-5 criteria. CDR ratings for DLB participants ranged from 0.5 to 2. The active tDCS (or sham) process consists of daily sessions of active tDCS (or sham) for 10 consecutive days. The anodal electrode was placed over the left DLPFC and the cathodal electrode was placed over the right supraorbital area, with a current intensity of 2 mA and an electrode size of 25 cm2 for 30 min in a session. Before and after these treatment sessions, all subjects received a series of neuropsychological tests, including CDR, MMSE, CASI, NPI and WCST. Chi-square test, Wilcoxon signed ranks test and Mann-Whitney U test were used to assess differences in participant demographic characteristics and to compare differences among groups.Results:The active tDCS group showed significant improvements on the three items of CASI, ‘language ability’, ‘concentration and calculation’, ‘categorical verbal fluency’, after active stimulations. There is no improvement in MMSE, CASI, NPI and WCST scores in the sham groups.Conclusion:These results suggest that left DLPFC anodal, and right deltoid cathodal tDCS, may have some cognitive benefits in DLB. Larger-scale trials are needed to confirm the effect of tDCS in DLB.Key words: Transcranial Direct Current Stimulation, Dementia with Lewy Bodies, cognitive function, Wisconsin Card Sorting Test, left DLPFC

Arc expression regulates long-term potentiation magnitude and metaplasticity in area CA1 of the hippocampus in ArcKR mice.

Expression of the immediate early gene Arc/Arg3.1 (Arc), a key mediator of synaptic plasticity, is enhanced by neural activity and then reduced by proteasome-dependent degradation. We have previously shown that the disruption of Arc degradation, in an Arc knock-in mouse (ArcKR), where the predominant Arc ubiquitination sites were mutated, reduced the threshold to induce, and also enhanced, the strength of Group I metabotropic glutamate receptor-mediated long-term depression (DHPG-LTD). Here, we have investigated if ArcKR expression changes long-term potentiation (LTP) in CA1 area of the hippocampus. As previously reported, there was no change in basal synaptic transmission at Schaffer collateral/commissural-CA1 (SC-CA1) synapses in ArcKR versus wild-type (WT) mice. There was, however, a significant increase in the amplitude of synaptically induced (with low frequency paired-pulse stimulation) LTD in ArcKR mice. Theta burst stimulation (TBS)-evoked LTP at SC-CA1 synapses was significantly reduced in ArcKR versus WT mice (after 2 h). Group 1 mGluR priming of LTP was abolished in ArcKR mice, which could also potentially contribute to a depression of LTP. Although high frequency stimulation (HFS)-induced LTP was not significantly different in ArcKR compared with WT mice (after 1h), there was a phenotype in environmentally enriched mice, with the ratio of LTP to short-term potentiation (STP) significantly reduced in ArcKR mice. These findings support the hypothesis that Arc ubiquitination supports the induction and expression of LTP, likely via limiting Arc-dependent removal of AMPA receptors at synapses.

Preventive exercise and physical rehabilitation promote long-term potentiation-like plasticity expression in patients with multiple sclerosis.

Loss of long-term potentiation (LTP) expression has been associated with a worse disease course in relapsing-remitting multiple sclerosis (RR-MS) and represents a pathophysiological hallmark of progressive multiple sclerosis (PMS). Exercise and physical rehabilitation are the most prominent therapeutic approaches to promote synaptic plasticity. We aimed to explore whether physical exercise is able to improve the expression of LTP-like plasticity in patients with multiple sclerosis (MS). In 46 newly diagnosed RR-MS patients, we explored the impact of preventive exercise on LTP-like plasticity as assessed by intermittent theta-burst stimulation. Patients were divided into sedentary or active, based on physical activity performed during the 6 months prior to diagnosis. Furthermore, in 18 patients with PMS, we evaluated the impact of an 8-week inpatient neurorehabilitation program on clinical scores and LTP-like plasticity explored using paired associative stimulation (PAS). Synaptic plasticity expression was compared in patients and healthy subjects. Reduced LTP expression was found in RR-MS patients compared with controls. Exercising RR-MS patients showed a greater amount of LTP expression compared with sedentary patients. In PMS patients, LTP expression was reduced compared with controls and increased after 8 weeks of rehabilitation. In this group of patients, LTP magnitude at baseline predicted the improvement in hand dexterity. Both preventive exercise and physical rehabilitation may enhance the expression of LTP-like synaptic plasticity in MS, with potential beneficial effects on disability accumulation.

Coenzyme Q10 supplementation improves the motor function of middle-aged mice by restoring the neuronal activity of the motor cortex

Physiological aging causes motor function decline and anatomical and biochemical changes in the motor cortex. We confirmed that middle-aged mice at 15–18 months old show motor function decline, which can be restored to the young adult level by supplementing with mitochondrial electron transporter coenzyme Q10 (CoQ10) as a water-soluble nanoformula by drinking water for 1 week. CoQ10 supplementation concurrently improved brain mitochondrial respiration but not muscle strength. Notably, we identified an age-related decline in field excitatory postsynaptic potential (fEPSP) amplitude in the pathway from layers II/III to V of the primary motor area of middle-aged mice, which was restored to the young adult level by supplementing with CoQ10 for 1 week but not by administering CoQ10 acutely to brain slices. Interestingly, CoQ10 with high-frequency stimulation induced NMDA receptor-dependent long-term potentiation (LTP) in layer V of the primary motor cortex of middle-aged mice. Importantly, the fEPSP amplitude showed a larger input‒output relationship after CoQ10-dependent LTP expression. These data suggest that CoQ10 restores the motor function of middle-aged mice by improving brain mitochondrial function and the basal fEPSP level of the motor cortex, potentially by enhancing synaptic plasticity efficacy. Thus, CoQ10 supplementation may ameliorate the age-related decline in motor function in humans.

Underlying mechanisms of long-term potentiation during the inhibition of the cannabinoid CB1 and GABAB receptors in the dentate gyrus of hippocampus

BackgroundThe release of various neurotransmitters and thereby the excitability of neuronal circuits are regulated by the endocannabinoid system in an activity-dependent manner. Hippocampal long-term potentiation (LTP) is augmented in cannabinoid type 1 (CB1) receptor-deficient mice. CB1 receptors exist on GABAergic axon terminals in the hippocampus. In our previous work, we showed that CB1 antagonists increased the population spike (PS) amplitude, field excitatory post-synaptic potential (fEPSP), and the LTP induction in the dentate gyrus (DG) of the rat hippocampus while the GABAB antagonist decreased these parameters. Determining the underlying mechanisms of the pre- and/or postsynaptic locus of LTP expression is of great importance. In this study, we investigated whether LTP alteration acutely caused by CB1 and GABAB receptor antagonists (AM251 and CGP55845, respectively) happens at the postsynaptic or presynaptic regions, or at both. Therefore, the paired-pulse ratio (PPR) was assessed prior to and following the LTP induction in the studied groups.MethodsMale Wistar rats were randomly assigned to the groups of control, AM251, CGP55845, CGP55845 + AM251. A high-frequency stimulation (HFS) of the perforant path (PP) was used to induce LTP in the DG region.ResultsStatistical analysis revealed that AM251 produced significant increase in excitatory postsynaptic potential (EPSP) slope and amplitude of PS. Conversely, administration of CGP55845 produced decrease in slope of EPSP. The current results indicated that the PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination.ConclusionsIt can be concluded that the site causing LTP expression is, at least in part, the postsynaptic site because PPR was not influenced by LTP induction in the presence of AM251 or CGP55845 either alone or their combination.

Lactate supply overtakes glucose when neural computational and cognitive loads scale up

Neural computational power is determined by neuroenergetics, but how and which energy substrates are allocated to various forms of memory engram is unclear. To solve this question, we asked whether neuronal fueling by glucose or lactate scales differently upon increasing neural computation and cognitive loads. Here, using electrophysiology, two-photon imaging, cognitive tasks, and mathematical modeling, we show that both glucose and lactate are involved in engram formation, with lactate supporting long-term synaptic plasticity evoked by high-stimulation load activity patterns and high attentional load in cognitive tasks and glucose being sufficient for less demanding neural computation and learning tasks. Indeed, we show that lactate is mandatory for demanding neural computation, such as theta-burst stimulation, while glucose is sufficient for lighter forms of activity-dependent long-term potentiation (LTP), such as spike timing-dependent plasticity (STDP). We find that subtle variations of spike number or frequency in STDP are sufficient to shift the on-demand fueling from glucose to lactate. Finally, we demonstrate that lactate is necessary for a cognitive task requiring high attentional load, such as the object-in-place task, and for the corresponding invivo hippocampal LTP expression but is not needed for a less demanding task, such as a simple novel object recognition. Overall, these results demonstrate that glucose and lactate metabolism are differentially engaged in neuronal fueling depending on the complexity of the activity-dependent plasticity and behavior.

Presynaptic HCN channel activity is required for the expression of long-term potentiation at lateral amygdala to basal amygdala synapses

Recently, we reported that auditory fear conditioning leads to the presynaptic potentiation at lateral amygdala to basal amygdala (LA-BA) synapses that shares the mechanism with high-frequency stimulation (HFS)-induced long-term potentiation (LTP) ex vivo. In the present study, we further examined the molecular mechanisms underlying the HFS-induced presynaptic LTP. We found that a presynaptic elevation of Ca2+ was required for the LTP induction. Interestingly, the blockade of presynaptic but not postsynaptic HCN channels with ZD7288 completely abolished LTP induction. While ZD7288 did not alter basal synaptic transmission, the blocker fully reversed previously established LTP, indicating that HCN channels are also required for the maintenance of LTP. Indeed, HCN3 and HCN4 channels were preferentially localized in the presynaptic boutons of LA afferents. Furthermore, an inhibition of either GABAB receptors or GIRK channels eliminated the inhibitory effect of HCN blockade on the LTP induction. Collectively, we suggest that activation of presynaptic HCN channels may counteract membrane hyperpolarization during tetanic stimulation, and thereby contributes to the presynaptic LTP at LA-BA synapses.

CREB serine 133 is necessary for spatial cognitive flexibility and long-term potentiation

The transcription factor cAMP response element-binding protein (CREB) is widely regarded as orchestrating the genomic response that underpins a range of physiological functions in the central nervous system, including learning and memory. Of the means by which CREB can be regulated, emphasis has been placed on the phosphorylation of a key serine residue, S133, in the CREB protein, which is required for CREB-mediated transcriptional activation in response to a variety of activity-dependent stimuli. Understanding the role of CREB S133 has been complicated by molecular genetic techniques relying on over-expression of either dominant negative or activating transgenes that may distort the physiological role of endogenous CREB. A more elegant recent approach targeting S133 in the endogenous CREB gene has yielded a mouse with constitutive replacement of this residue with alanine (S133A), but has generated results (no behavioural phenotype and no effect on gene transcription) at odds with contemporary views as to the role of CREB S133, and which may reflect compensatory changes associated with the constitutive mutation. To avoid this potential complication, we generated a post-natal and forebrain-specific CREB S133A mutant in which the expression of the mutation was under the control of CaMKIIα promoter. Using male and female mice we show that CREB S133 is necessary for spatial cognitive flexibility, the regulation of basal synaptic transmission, and for the expression of long-term potentiation (LTP) in hippocampal area CA1. These data point to the importance of CREB S133 in neuronal function, synaptic plasticity and cognition in the mammalian brain.

Stress Affects Central Compensation of Neural Responses to Cochlear Synaptopathy in a cGMP-Dependent Way.

In light of the increasing evidence supporting a link between hearing loss and dementia, it is critical to gain a better understanding of the nature of this relationship. We have previously observed that following cochlear synaptopathy, the temporal auditory processing (e.g., auditory steady state responses, ASSRs), is sustained when reduced auditory input is centrally compensated. This central compensation process was linked to elevated hippocampal long-term potentiation (LTP). We further observed that, independently of age, central responsiveness to cochlear synaptopathy can differ, resulting in either a low or high capacity to compensate for the reduced auditory input. Lower central compensation resulted in poorer temporal auditory processing, reduced hippocampal LTP, and decreased recruitment of activity-dependent brain-derived neurotrophic factor (BDNF) expression in hippocampal regions (low compensators). Higher central compensation capacity resulted in better temporal auditory processing, higher LTP responses, and increased activity-dependent BDNF expression in hippocampal regions. Here, we aimed to identify modifying factors that are potentially responsible for these different central responses. Strikingly, a poorer central compensation capacity was linked to lower corticosterone levels in comparison to those of high compensators. High compensators responded to repeated placebo injections with elevated blood corticosterone levels, reduced auditory brainstem response (ABR) wave I amplitude, reduced inner hair cell (IHC) ribbon number, diminished temporal processing, reduced LTP responses, and decreased activity-dependent hippocampal BDNF expression. In contrast, the same stress exposure through injection did not elevate blood corticosterone levels in low compensators, nor did it reduce IHC ribbons, ABR wave I amplitude, ASSR, LTP, or BDNF expression as seen in high compensators. Interestingly, in high compensators, the stress-induced responses, such as a decline in ABR wave I amplitude, ASSR, LTP, and BDNF could be restored through the “memory-enhancing” drug phosphodiesterase 9A inhibitor (PDE9i). In contrast, the same treatment did not improve these aspects in low compensators. Thus, central compensation of age-dependent cochlear synaptopathy is a glucocorticoid and cyclic guanosine-monophosphate (cGMP)-dependent neuronal mechanism that fails upon a blunted stress response.

High-resolution imaging and manipulation of endogenous AMPA receptor surface mobility during synaptic plasticity and learning.

Regulation of synaptic neurotransmitter receptor content is a fundamental mechanism for tuning synaptic efficacy during experience-dependent plasticity and behavioral adaptation. However, experimental approaches to track and modify receptor movements in integrated experimental systems are limited. Exploiting AMPA-type glutamate receptors (AMPARs) as a model, we generated a knock-in mouse expressing the biotin acceptor peptide (AP) tag on the GluA2 extracellular N-terminal. Cell-specific introduction of biotin ligase allows the use of monovalent or tetravalent avidin variants to respectively monitor or manipulate the surface mobility of endogenous AMPAR containing biotinylated AP–GluA2 in neuronal subsets. AMPAR immobilization precluded the expression of long-term potentiation and formation of contextual fear memory, allowing target-specific control of the expression of synaptic plasticity and animal behavior. The AP tag knock-in model offers unprecedented access to resolve and control the spatiotemporal dynamics of endogenous receptors, and opens new avenues to study the molecular mechanisms of synaptic plasticity and learning.

STAT4 Play A Critical Role in Aging and High Fat Diet‐Associated Decline in Long‐Term, Activity‐Dependent Potentiation of Synaptic Transmission

Aging and Alzheimer’s disease (AD) both exhibit declines in the magnitude of long‐term, activity‐dependent synaptic potentiation in humans and animals that correlate with declines in cognitive function and long‐term memory in a range of behavioral tasks. Signal Transducer and Activator of Transcription 4 (STAT4) is a transcription factor that is essential for mediating T helper 1 cell differentiation and induction of inflammatory responses to IL‐12. STAT4 plays a vital role in signaling in a range of inflammatory diseases, including cardiovascular inflammation in diabetes, systemic lupus erythematosus and rheumatoid arthritis. It is, however, unknown what role STAT4 plays in central nervous system diseases such as AD, which also have significant inflammatory components to the progression of neurodegeneration. The present study examined the effects of elimination of STAT4 signaling in transgenic mice lacking myeloid cell‐specific STAT4 expression on the expression of long‐term potentiation (LTP) of synaptic transmission, and learning and memory, in mice fed normal versus high‐fat diets. Electrophysiological recordings from Schaffer collateral‐CA1 synapses in hippocampal slices from 3 or 24 week old LysMcreStat4fl/flLdlr‐/‐ mice showed no differences in baseline synaptic transmission, paired‐pulse facilitation (PPF, a measure of presynaptic function), or LTP compared to age‐matched Stat4fl/flLdlr‐/‐ control littermates. Feeding mice a high cholesterol, high carbohydrate diet (DDC) diet from 8‐24 weeks of age resulted in marked, significant impairments in LTP compared to age‐matched mice fed a chow diet, without differences in basal transmission or PPF. In contrast to Stat4fl/flLdlr‐/‐ control mice, LysMcreStat4fl/flLdlr‐/‐ mice receiving the same DDC diet were completely protected from DDC‐associated reductions in LTP. Our current behavioral data support the idea that DDC fed Ldlr‐/‐ mice may experience cognitive and memory declines associated with early AD in comparison with LysMcreStat4fl/flLdlr‐/‐ mice. Taken together, our data support an essential role for the transcription factor STAT4 in the sensitivity of the central nervous system to DDC ‐induced impairments in synaptic plasticity and potentially cognitive function, and suggest that STAT4 pathways are a promising new target for interventions to treat neurodegenerative diseases such as Alzheimer’s, where chronic neuroinflammation is a critical disease mediator.

Synaptic plasticity in hippocampal CA1 neurons of mice lacking inositol-1,4,5-trisphosphate receptor-binding protein released with IP3 (IRBIT).

In hippocampal CA1 neurons of wild-type mice, a short tetanus (15 or 20 pulses at 100 Hz) or a standard tetanus (100 pulses at 100 Hz) to a naive input pathway induces long-term potentiation (LTP) of the responses. Low-frequency stimulation (LFS; 1000 pulses at 1 Hz) 60 min after the standard tetanus reverses LTP (depotentiation [DP]), while LFS applied 60 min prior to the standard tetanus suppresses LTP induction (LTP suppression). We investigated LTP, DP, and LTP suppression of both field excitatory postsynaptic potentials and population spikes in CA1 neurons of mice lacking the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R)-binding protein released with IP3 (IRBIT). The mean magnitudes of LTP induced by short and standard tetanus were not different in mutant and wild-type mice. In contrast, DP and LTP suppression were attenuated in mutant mice, whereby the mean magnitude of responses after LFS or tetanus were significantly greater than in wild-type mice. These results suggest that, in hippocampal CA1 neurons, IRBIT is involved in DP and LTP suppression, but is not essential for LTP. The attenuation of DP and LTP suppression in mice lacking IRBIT indicates that this protein, released during or after priming stimulations, determines the direction of LTP expression after the delivery of subsequent stimulations.

40 Hz Light Flicker Promotes Learning and Memory via Long Term Depression in Wild-Type Mice.

40 Hz light flicker is a well-known non-invasive treatment that is thought to be effective in treating Alzheimer's disease. However, the effects of 40 Hz visual stimulation on neural networks, synaptic plasticity, and learning and memory in wild-type animals remain unclear. We aimed to explore the impact of 40 Hz visual stimulation on synaptic plasticity, place cell, and learning and memory in wild-type mice. c-Fos+ cell distribution and in vivo electrophysiology was used to explore the effects of 40 Hz chronic visual stimulation on neural networks and neuroplasticity in wild-type mice. The character of c-Fos+ distribution in the brain and the changes of corticosterone levels in the blood were used to investigate the state of animal. Place cell analysis and novel location test were utilized to examine the effects of 40 Hz chronic visual stimulation on learning and memory in wild-type mice. We found that 40 Hz light flicker significantly affected many brain regions that are related to stress. Also, 40 Hz induced gamma enrichment within 15 min after light flickers and impaired the expression of long-term potentiation (LTP), while facilitated the expression of long-term depression (LTD) in the hippocampal CA1. Furthermore, 40 Hz light flicker enhanced the expression of corticosterone, rendered well-formed place cells unstable and improved animal's learning and memory in novel local recognition test, which could be blocked by pre-treatment with the LTD specific blocker Glu2A-3Y. These finding suggested that 40 Hz chronic light flicker contains stress effects, promoting learning and memory in wild-type mice via LTD.

419 - Effect of Transcranial Direct Current Stimulation (tDCS) in Dementia with Lewy Bodies

AbstractIntroduction:Dementia with Lewy Bodies (DLB), this second most common form of degenerative dementia, presents more functional disability, more potentially fatal complication, more impaired quality of life than Alzheimer’s dementia. There is no FDA-proved medication can slow, stop or improve the progression of cognitive declines in DLB. Identifying effective treatments is a critical issue for DLB. In neuropathology, extracelluar α-syn oligomers interfere with the expression of long-term potentiation, and influence memory and learning. Transcranial direct current stimulation (tDCS) has been proposed to affect long-term synaptic plasticity through LTP and LTD, thereby improving cognitive ability. So far, only two researches assess the effect of tDCS in DLB. In this pilot study, we investigate the effects of tDCS in DLB.Method:Using a double-blind, randomized, sham- controlled and crossover trial design, 11 DLB aged 55-90 years (mean age 77.8) were included in the study. DLB diagnostics is according to DSM-5 criteria. The CDR ratings of DLB participants ranged from 0.5 to 2. The active tDCS (or sham) process includes consecutive daily sessions of active tDCS (or sham) for 10 days. The anodal electrode was over the left dorsal lateral prefrontal cortex (DLPFC) and the cathodal electrode on the right supraorbital area. In each session, we applied a current intensity of 2 mA and an electrode size of 25 cm2 for 30 min in the active group. All subjects received a series of neuropsychological tests, which included CDR, MMSE, CASI, NPI and WCST, before and after these treatment sessions. Chi-square tests, Wilcoxon signed rank tests and Mann-Whitney U tests were used to assess the differences in participant demographic characteristics and to compare the differences among groups.Results:On CASI, MMSE, NPI and WCST, there were no statistically significant differences between pre- and post the 10-session course for the active and the sham groups. No side effects reported during or immediately after active tDCS stimulation.Conclusion:These results suggest that left DLPFC anodal, and right deltoid cathodal tDCS, do not improve cognition, behavioral and psychological symptoms in DLB. Larger-scale trials are needed to confirm the effect of tDCS in DLB.

The vSNAREs VAMP2 and VAMP4 control recycling and intracellular sorting of post-synaptic receptors in neuronal dendrites.

The endosomal recycling system dynamically tunes synaptic strength, which underlies synaptic plasticity. Exocytosis is involved in the expression of long-term potentiation (LTP), as postsynaptic cleavage of the SNARE (soluble NSF-attachment protein receptor) protein VAMP2 by tetanus toxin blocks LTP. Moreover, induction of LTP increases the exocytosis of transferrin receptors (TfRs) and markers of recycling endosomes (REs), as well as post-synaptic AMPA type receptors (AMPARs). However, the interplay between AMPAR and TfR exocytosis remains unclear. Here, we identify VAMP4 as the vesicular SNARE that mediates most dendritic RE exocytosis. In contrast, VAMP2 plays a minor role in RE exocytosis. LTP induction increases the exocytosis of both VAMP2- and VAMP4-labeled organelles. Knock down (KD) of VAMP4 decreases TfR recycling but increases AMPAR recycling. Moreover, VAMP4 KD increases AMPAR-mediated synaptic transmission, which consequently occludes LTP expression. The opposing changes in AMPAR and TfR recycling upon VAMP4 KD reveal their sorting into separate endosomal populations.

Hippocampal CA1 theta burst-induced LTP from weaning to adulthood: Cellular and molecular mechanisms in young male rats revisited.

Long-term potentiation (LTP) is a highly studied cellular process, yet determining the transduction and gamma aminobutyric acid (GABAergic) pathways that are the essential versus modulatory for LTP elicited by theta burst stimulation (TBS) in the hippocampal Cornu Ammonis 1 (CA1) area is still elusive, due to the use of different TBS intensities, patterns or different rodent/cellular models. We now characterised the developmental maturation and the transduction and GABAergic pathways required for mild TBS-induced LTP in hippocampal CA1 area in male rats. LTP induced by TBS (5x4) (five bursts of four pulses delivered at 100 Hz) lasted for up to 3 h and was increasingly larger from weaning to adulthood. Stronger TBS patterns - TBS (15x4) or three TBS (15x4) separated by 6 min induced nearly maximal LTP not being the best choice to study the value of LTP-enhancing drugs. LTP induced by TBS (5x4) in young adults was fully dependent on N-methyl D-aspartate (NMDA) receptor and calmodulin-dependent protein kinase II (CaMKII) activity but independent of protein kinase A (PKA) or protein kinase C (PKC) activity. Furthermore, it was partially dependent on GABAB receptor activation and was potentiated by GABAA receptor blockade and less by GAT-1 transporter blockade. AMPA GluA1 phosphorylation on Ser831 (CaMKII target) but not GluA1 Ser845 (PKA target) was essential for LTP expression. The phosphorylation of the Kv4.2 channel was observed at Ser438 (CaMKII target) but not at Thr602 or Thr607 (ERK/MAPK pathway target). This suggests that cellular kinases like PKA, PKC, or kinases of the ERK/MAPK family although important modulators of TBS (5x4)-induced LTP may not be essential for its expression in the CA1 area of the hippocampus.

Neuronal activity-induced SUMOylation of Akt1 by PIAS3 is required for long-term potentiation of synaptic transmission.

Neuronal activity regulates spatial distribution of the SUMOylation system in cytosolic and dendritic sites, which has been implicated in learning, memory, and underlying synaptic structural and functional remodeling in the hippocampus. However, the functional target proteins for activated small ubiquitin-like modifiers (SUMOs) and downstream molecular consequences behind long-term potentiation (LTP) of synaptic plasticity remain to be elucidated. In this study, we showed that N-methyl-D-aspartate receptor-mediated neuronal activity induced the covalent modification of cytosolic Akt1 by small ubiquitin-like modifier 1 (SUMO1) in rat cortical and hippocampal CA1 neurons. Protein inhibitor of activated STAT3 (PIAS3) was involved in the activity-induced Akt1 SUMO1-ylation, and K64 and K276 residues were major SUMOylated sites. Importantly, Akt1 SUMOylation at K64 and K276 enhanced its enzymatic activity and facilitated T308 phosphorylation. Furthermore, the N-terminal SAP domain of PIAS3 bound Akt1 directly. The disruption of Akt1-PIAS3 interaction by Tat-SAP, a synthetic Tat-fused cell-permeable peptide containing PIAS3 SAP domain, inhibited neuronal activity-induced Akt1 SUMOylation and impaired LTP expression and late phase LTP maintenance in the hippocampus. Correlatedly, Tat-SAP not only blocked the LTP-related extracellular signal-regulated kinase (ERK)1/2-Elk-1-brain-derived neurotrophic factor (BDNF)/Arc signaling, but also disrupted mammalian target of rapamycin (mTOR)-eIF4E-binding protein 1 (4E-BP1) pathway. These findings reveal an activity-induced Akt1 SUMOylation by PIAS3 that contributes to ERK1/2-BDNF/Arc and mTOR-4E-BP1 cascades, and in turn, long-lasting excitatory synaptic responses.