Inhibition of Nogo-A rescues synaptic plasticity and associativity in APP/PS1 animal model of Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by memory loss and cognitive decline. Synaptic impairment is one of the first events to occur in the progression of this disease. Synaptic plasticity and cellular association of various plastic events have been shown to be affected in AD models. Nogo-A, a well-known axonal growth inhibitor with a recently discovered role as a plasticity suppressor, and its main receptor Nogo-66 receptor 1 (NGR1) have been found to be overexpressed in the hippocampus of Alzheimer's patients. However, the role of Nogo-A and its receptor in the pathology of AD is still widely unknown. In this work we set out to investigate whether Nogo-A is working as a plasticity suppressor in AD. Our results show that inhibition of the Nogo-A pathway via the Nogo-R antibody in an Alzheimer's mouse model, APP/PS1, leads to the restoration of both synaptic plasticity and associativity in a protein synthesis and NMDR-dependent manner. We also show that inhibition of the p75NTR pathway, which is strongly associated with NGR1, restores synaptic plasticity as well. Mechanistically, we propose that the restoration of synaptic plasticity in APP/PS1 via inhibition of the Nogo-A pathway is due to the modulation of the RhoA-ROCK2 pathway and increase in plasticity related proteins. Our study identifies Nogo-A as a plasticity suppressor in AD models hence targeting Nogo-A could be a promising strategy to understanding AD pathology.

Inactive variants of death receptor p75NTR reduce Alzheimer's neuropathology by interfering with APP internalization.

A prevalent model of Alzheimer's disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. The molecular pathways that regulate APP internalization and intracellular trafficking in neurons are incompletely understood. Here, we report that 5xFAD mice, an animal model of AD, expressing signaling-deficient variants of the p75 neurotrophin receptor (p75NTR ) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75NTR knock-in mice lacking the death domain or transmembrane Cys259 showed lower levels of Aß species, amyloid plaque burden, gliosis, mitochondrial stress, and neurite dystrophy than global knock-outs. Strikingly, long-term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock-in mice. Mechanistically, we found that p75NTR interacts with APP at the plasma membrane and regulates its internalization and intracellular trafficking in hippocampal neurons. Inactive p75NTR variants internalized considerably slower than wild-type p75NTR and showed increased association with the recycling pathway, thereby reducing APP internalization and co-localization with BACE1, the critical protease for generation of neurotoxic APP fragments, favoring non-amyloidogenic APP cleavage. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing, and disease progression, and suggest that inhibitors targeting the p75NTR transmembrane domain may be an effective therapeutic strategy in AD.

Loss of CaV1.3 RNA editing enhances mouse hippocampal plasticity, learning, and memory.

L-type CaV1.3 calcium channels are expressed on the dendrites and soma of neurons, and there is a paucity of information about its role in hippocampal plasticity. Here, by genetic targeting to ablate CaV1.3 RNA editing, we demonstrate that unedited CaV1.3ΔECS mice exhibited improved learning and enhanced long-term memory, supporting a functional role of RNA editing in behavior. Significantly, the editing paradox that functional recoding of CaV1.3 RNA editing sites slows Ca2+-dependent inactivation to increase Ca2+ influx but reduces channel open probability to decrease Ca2+ influx was resolved. Mechanistically, using hippocampal slice recordings, we provide evidence that unedited CaV1.3 channels permitted larger Ca2+ influx into the hippocampal pyramidal neurons to bolster neuronal excitability, synaptic transmission, late long-term potentiation, and increased dendritic arborization. Of note, RNA editing of the CaV1.3 IQ-domain was found to be evolutionarily conserved in mammals, which lends support to the importance of the functional recoding of the CaV1.3 channel in brain function.

Nogo-A-mediated constraints on activity-dependent synaptic plasticity and associativity in rat hippocampal CA2 synapses.

Hippocampal area CA2 has garnered attention in recent times owing to its significant involvement in social memory and distinctive plasticity characteristics. Research has revealed that the CA2 region demonstrates a remarkable resistance to plasticity, particularly in the Schaffer Collateral (SC)-CA2 pathway. In this study we investigated the role of Nogo-A, a well-known axon growth inhibitor and more recently discovered plasticity regulator, in modulating plasticity within the CA2 region. The findings demonstrate that blocking Nogo-A in male rat hippocampal slices facilitates the establishment of both short-term and long-term plasticity in the SC-CA2 pathway, while having no impact on the Entorhinal Cortical (EC)-CA2 pathway. Additionally, the study reveals that inhibiting Nogo-A enables association between the SC and EC pathways. Mechanistically, we confirm that Nogo-A operates through its well-known co-receptor, p75 neurotrophin receptor (p75NTR), and its downstream signaling factor such as Rho-associated protein kinase (ROCK), as their inhibition also allows plasticity induction in the SC-CA2 pathway. Additionally, the induction of long-term depression (LTD) in both the EC and SC-CA2 pathways led to persistent LTD, which was not affected by Nogo-A inhibition. Our study demonstrates the involvement of Nogo-A mediated signaling mechanisms in limiting synaptic plasticity within the CA2 region.

Aging inverts the effects of p75NTR -modulated mTOR manipulation on hippocampal neuron synaptic plasticity in male mice.

Age-induced impairments in learning and memory are in part caused by changes to hippocampal synaptic plasticity during aging. The p75 neurotrophin receptor (p75NTR ) and mechanistic target of rapamycin (mTOR) are implicated in synaptic plasticity processes. mTOR is also well known for its involvement in aging. Recently, p75NTR and mTOR were shown to be mechanistically linked, and that p75NTR mediates age-induced impairment of hippocampal synaptic plasticity. Yet the consequences of p75NTR -mTOR interaction on hippocampal synaptic plasticity, and the role of mTOR in age-induced cognitive decline, are unclear. In this study, we utilize field electrophysiology to study the effects of mTOR inhibition and activation on long-term potentiation (LTP) in male young and aged wild-type (WT) mice. We then repeated the experiments on p75NTR knockout mice. The results demonstrate that mTOR inhibition blocks late-LTP in young WT mice but rescues age-related late-LTP impairment in aged WT mice. mTOR activation suppresses late-LTP in aged WT mice while lacking observable effects on young WT mice. These effects were not observed in p75NTR knockout mice. These results demonstrate that the role of mTOR in hippocampal synaptic plasticity is distinct between young and aged mice. Such effects could be explained by differing sensitivity of young and aged hippocampal neurons to changes in protein synthesis or autophagic activity levels. Additionally, elevated mTOR in the aged hippocampus could cause excessive mTOR signaling, which is worsened by activation and alleviated by inhibition. Further research on mTOR and p75NTR may prove useful for advancing understanding and, ultimately, mitigation of age-induced cognitive decline.

Hydroxychloroquine lowers Alzheimer's disease and related dementias risk and rescues molecular phenotypes related to Alzheimer's disease.

We recently nominated cytokine signaling through the Janus-kinase-signal transducer and activator of transcription (JAK/STAT) pathway as a potential AD drug target. As hydroxychloroquine (HCQ) has recently been shown to inactivate STAT3, we hypothesized that it may impact AD pathogenesis and risk. Among 109,124 rheumatoid arthritis patients from routine clinical care, HCQ initiation was associated with a lower risk of incident AD compared to methotrexate initiation across 4 alternative analyses schemes addressing specific types of biases including informative censoring, reverse causality, and outcome misclassification (hazard ratio [95% confidence interval] of 0.92 [0.83-1.00], 0.87 [0.81-0.93], 0.84 [0.76-0.93], and 0.87 [0.75-1.01]). We additionally show that HCQ exerts dose-dependent effects on late long-term potentiation (LTP) and rescues impaired hippocampal synaptic plasticity prior to significant accumulation of amyloid plaques and neurodegeneration in APP/PS1 mice. Additionally, HCQ treatment enhances microglial clearance of Aß1-42, lowers neuroinflammation, and reduces tau phosphorylation in cell culture-based phenotypic assays. Finally, we show that HCQ inactivates STAT3 in microglia, neurons, and astrocytes suggesting a plausible mechanism associated with its observed effects on AD pathogenesis. HCQ, a relatively safe and inexpensive drug in current use may be a promising disease-modifying AD treatment. This hypothesis merits testing through adequately powered clinical trials in at-risk individuals during preclinical stages of disease progression.

Distinct contributions of ventral CA1/amygdala co-activation to the induction and maintenance of synaptic plasticity.

The amygdala is known to modulate hippocampal synaptic plasticity. One role could be an immediate effect of basolateral amygdala (BLA) in priming synaptic plasticity in the hippocampus. Another role could be through associative synaptic co-operation and competition that triggers events involved in the maintenance of synaptic potentiation. We present evidence that the timing and activity level of BLA stimulation are important factors for the induction and maintenance of long-term potentiation (LTP) in ventral hippocampal area CA1. A 100 Hz BLA co-stimulation facilitated the induction of LTP, whereas 200 Hz co-stimulation attenuated induction. A 100 Hz BLA co-stimulation also caused enhanced persistence, sufficient to prevent synaptic competition. This maintenance effect is likely through translational mechanisms, as mRNA expression of primary response genes was unaffected, whereas protein level of plasticity-related products was increased. Further understanding of the neural mechanisms of amygdala modulation on hippocampus could provide insights into the mechanisms of emotional disorders.

Alteration of hippocampal CA2 plasticity and social memory in adult rats impacted by juvenile stress.

The hippocampal CA2 region has received greater attention in recent years due to its fundamental role in social memory and hippocampus-dependent memory processing. Unlike entorhinal cortical inputs, the Schaffer collateral inputs to CA2 do not support activity-dependent long-term potentiation (LTP), which serves as the basis for long-term memories. This LTP-resistant zone also expresses genes that restrict plasticity. With the aim of exploring social interaction and sociability in rats that were subjected to juvenile stress, we addressed questions about how the neural circuitry is altered and its effects on social behavior. Although there was induction of LTP in both Schaffer collateral and entorhinal cortical pathways in juvenile-stressed rats, LTP declined in both pathways after 2-3 h. Moreover, exogenous bath application of substance P, a neuropeptide that resulted in slow onset long-lasting potentiation in control animals while it failed to induce LTP in juvenile-stressed rats. Our study reveals that juvenile-stressed rats show behavioral and cellular abnormalities with a long-lasting impact in adulthood.

Abnormal TDP-43 function impairs activity-dependent BDNF secretion, synaptic plasticity, and cognitive behavior through altered Sortilin splicing.

Aberrant function of the RNA-binding protein TDP-43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP-43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease-associated mutation of TDP-43 all impair intracellular sorting and activity-dependent secretion of the neurotrophin brain-derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP-43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF. Human neurons derived from patient iPSCs carrying mutated TDP-43 also show altered Sortilin splicing and reduced levels of activity-dependent BDNF secretion, which can be restored by correcting the mutation. We propose that major disease phenotypes caused by aberrant TDP-43 activity may be explained by the abnormal function of a handful of critical proteins, such as BDNF.

Metaplastic Reinforcement of Long-Term Potentiation in Hippocampal Area CA2 by Cholinergic Receptor Activation.

Hippocampal CA2, an inconspicuously positioned area between the well-studied CA1 and CA3 subfields, has captured research interest in recent years because of its role in social memory formation. However, the role of cholinergic inputs to the CA2 area for the regulation of synaptic plasticity remains to be fully understood. We show that cholinergic receptor activation with the nonselective cholinergic agonist, carbachol (CCh), triggers a protein synthesis-dependent and NMDAR-independent long-term synaptic depression (CCh-LTD) at entorhinal cortical (EC)-CA2 and Schaffer collateral (SC)-CA2 synapses in the hippocampus of adult male Wistar rats. The activation of muscarinic acetylcholine receptors (mAChRs) is critical for the induction of CCh-LTD with the results suggesting an involvement of M3 and M1 mAChRs in the early facilitation of CCh-LTD, while nicotinic AChR activation plays a role in the late maintenance of CCh-LTD at CA2 synapses. Remarkably, we find that CCh priming lowers the threshold for the subsequent induction of persistent long-term potentiation (LTP) of synaptic transmission at EC-CA2 and the plasticity-resistant SC-CA2 pathways. The effects of such a cholinergic-dependent synaptic depression on subsequent LTP at EC-CA2 and SC-CA2 synapses have not been previously explored. Collectively, the results demonstrate that CA2 synaptic learning rules are regulated in a metaplastic manner, whereby modifications triggered by prior cholinergic stimulation can dictate the outcome of future plasticity events. Moreover, the reinforcement of LTP at EC inputs to CA2 following the priming stimulus coexists with concurrent sustained CCh-LTD at the SC-CA2 pathway and is dynamically scaled by modulation of SC-CA2 synaptic transmission.SIGNIFICANCE STATEMENT The release of the neuromodulator acetylcholine is critically involved in processes of hippocampus-dependent memory formation. Cholinergic afferents originating in the medial septum and diagonal bands of Broca terminating in the hippocampal area CA2 might play an important role in the modulation of area-specific synaptic plasticity. Our findings demonstrate that cholinergic receptor activation induces an LTD of synaptic transmission at entorhinal cortical- and Schaffer collateral-CA2 synapses. This cholinergic activation-mediated LTD displays a bidirectional metaplastic switch to LTP on a future timescale. This suggests that such bidirectional synaptic modifications triggered by the dynamic modulation of tonic cholinergic receptor activation may support the formation of CA2-dependent memories given the increased hippocampal cholinergic tone during active wakefulness observed in exploratory behavior.

Inhibitory Metaplasticity in Juvenile Stressed Rats Restores Associative Memory in Adulthood by Regulating Epigenetic Complex G9a/GLP.

BACKGROUND: Exposure to juvenile stress was found to have long-term effects on the plasticity and quality of associative memory in adulthood, but the underlying mechanisms are still poorly understood. METHODS: Three- to four week-old male Wistar rats were subjected to a 3-day juvenile stress paradigm. Their electrophysiological correlates of memory using the adult hippocampal slice were inspected to detect alterations in long-term potentiation and synaptic tagging and capture model of associativity. These cellular alterations were tied in with the behavioral outcome by subjecting the rats to a step-down inhibitory avoidance paradigm to measure strength in their memory. Given the role of epigenetic response in altering plasticity as a repercussion of juvenile stress, we aimed to chart out the possible epigenetic marker and its regulation in the long-term memory mechanisms using quantitative reverse transcription polymerase chain reaction. RESULTS: We demonstrate that even long after the elimination of actual stressors, an inhibitory metaplastic state is evident, which promotes synaptic competition over synaptic cooperation and decline in latency of associative memory in the behavioral paradigm despite the exposure to novelty. Mechanistically, juvenile stress led to a heightened expression of the epigenetic marker G9a/GLP complex, which is thus far ascribed to transcriptional silencing and goal-directed behavior. CONCLUSIONS: The blockade of the G9a/GLP complex was found to alleviate deficits in long-term plasticity and associative memory during the adulthood of animals exposed to juvenile stress. Our data provide insights on the long-term effects of juvenile stress that involve epigenetic mechanisms, which directly impact long-term plasticity, synaptic tagging and capture, and associative memory.

Long-term population spike-timing-dependent plasticity promotes synaptic tagging but not cross-tagging in rat hippocampal area CA1.

In spike-timing-dependent plasticity (STDP), the direction and degree of synaptic modification are determined by the coherence of pre- and postsynaptic activities within a neuron. However, in the adult rat hippocampus, it remains unclear whether STDP-like mechanisms in a neuronal population induce synaptic potentiation of a long duration. Thus, we asked whether the magnitude and maintenance of synaptic plasticity in a population of CA1 neurons differ as a function of the temporal order and interval between pre- and postsynaptic activities. Modulation of the relative timing of Schaffer collateral fibers (presynaptic component) and CA1 axons (postsynaptic component) stimulations resulted in an asymmetric population STDP (pSTDP). The resulting potentiation in response to 20 pairings at 1 Hz was largest in magnitude and most persistent (4 h) when presynaptic activity coincided with or preceded postsynaptic activity. Interestingly, when postsynaptic activation preceded presynaptic stimulation by 20 ms, an immediate increase in field excitatory postsynaptic potentials was observed, but it eventually transformed into a synaptic depression. Furthermore, pSTDP engaged in selective forms of late-associative activity: It facilitated the maintenance of tetanization-induced early long-term potentiation (LTP) in neighboring synapses but not early long-term depression, reflecting possible mechanistic differences with classical tetanization-induced LTP. The data demonstrate that a pairing of pre- and postsynaptic activities in a neuronal population can greatly reduce the required number of synaptic plasticity-evoking events and induce a potentiation of a degree and duration similar to that with repeated tetanization. Thus, pSTDP determines synaptic efficacy in the hippocampal CA3-CA1 circuit and could bias the CA1 neuronal population toward potentiation in future events.

Regulation of aberrant proteasome activity re-establishes plasticity and long-term memory in an animal model of Alzheimer's disease.

Reduced retrograde memory performance at the cognitive level and aggregation/deposition of amyloid beta (Aß) in the brain at the cellular level are some of the hallmarks of Alzheimer's Disease (AD). A molecular system that participates in the removal of proteins with an altered conformation is the Ubiquitin-Proteasome System (UPS). Impairments of the UPS in wild-type (WT) mice lead to defective clearance of Aß and prevent long-term plasticity of synaptic transmission. Here we show data whereby in contrast to WT mice, the inhibition of proteasome-mediated protein degradation in an animal model of AD by MG132 or lactacystin restores impaired activity-dependent synaptic plasticity and its associative interaction, synaptic tagging and capture (STC) in vitro, as well as associative long-term memory in vivo. This augmentation of synaptic plasticity and memory is mediated by the mTOR pathway and protein synthesis. Our data offer novel insights into the rebalancing of proteins relevant for synaptic plasticity which are regulated by UPS in AD-like animal models. In addition, the data provide evidence that proteasome inhibitors might be effective in reinstating synaptic plasticity and memory performance in AD, and therefore offer a new potential therapeutic option for AD treatment.

Inhibition of Histone Deacetylase Reinstates Hippocampus-Dependent Long-Term Synaptic Plasticity and Associative Memory in Sleep-Deprived Mice.

Sleep plays an important role in the establishment of long-term memory; as such, lack of sleep severely impacts domains of our health including cognitive function. Epigenetic mechanisms regulate gene transcription and protein synthesis, playing a critical role in the modulation of long-term synaptic plasticity and memory. Recent evidences indicate that transcriptional dysregulation as a result of sleep deprivation (SD) may contribute to deficits in plasticity and memory function. The histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA), also known as Vorinostat, a clinically approved drug for human use, has been shown to ameliorate cognitive deficits in several neurological disease models. To further explore the therapeutic effect of SAHA, we have examined its potential role in improving the SD-mediated impairments in long-term plasticity, associative plasticity, and associative memory. Here we show that SAHA preserves long-term plasticity, associative plasticity, and associative memory in SD hippocampus. Furthermore, we find that SAHA prevents SD-mediated epigenetic changes by upregulating histone acetylation, hence preserving the ERK-cAMP-responsive element-binding protein (CREB)/CREB-binding protein-brain-derived neurotrophic factor pathway in the hippocampus. These data demonstrate that modifying epigenetic mechanisms via SAHA can prevent or reverse impairments in long-term plasticity and memory that result from sleep loss. Thus, SAHA could be a potential therapeutic agent in improving SD-related memory deficits.

The p75 Neurotrophin Receptor Is an Essential Mediator of Impairments in Hippocampal-Dependent Associative Plasticity and Memory Induced by Sleep Deprivation.

Sleep deprivation (SD) interferes with hippocampal structural and functional plasticity, formation of long-term memory and cognitive function. The molecular mechanisms underlying these effects are incompletely understood. Here, we show that SD impaired synaptic tagging and capture and behavioral tagging, two major mechanisms of associative learning and memory. Strikingly, mutant male mice lacking the p75 neurotrophin receptor (p75NTR) were resistant to the detrimental effects of SD on hippocampal plasticity at both cellular and behavioral levels. Mechanistically, SD increased p75NTR expression and its interaction with phosphodiesterase. p75NTR deletion preserved hippocampal structural and functional plasticity by preventing SD-mediated effects on hippocampal cAMP-CREB-BDNF, cAMP-PKA-LIMK1-cofilin, and RhoA-ROCK2 pathways. Our study identifies p75NTR as an important mediator of hippocampal structural and functional changes associated with SD, and suggests that targeting p75NTR could be a promising strategy to limit the memory and cognitive deficits that accompany sleep loss.SIGNIFICANCE STATEMENT The lack of sufficient sleep is a major health concern in today's world. Sleep deprivation (SD) affects cognitive functions such as memory. We have investigated how associative memory mechanisms, synaptic tagging and capture (STC), was impaired in SD mice at cellular and behavioral level. Interestingly, mutant male mice that lacked the p75 neurotrophin receptor (p75NTR) were seen to be resistant to the SD-induced impairments in hippocampal synaptic plasticity and STC. Additionally, we elucidated the molecular pathways responsible for this rescue of plasticity in the mutant mice. Our study has thus identified p75NTR as a promising target to limit the cognitive deficits associated with SD.

Epigenetic regulation of microglial phosphatidylinositol 3-kinase pathway involved in long-term potentiation and synaptic plasticity in rats.

Microglia are the main form of immune defense in the central nervous system. Microglia express phosphatidylinositol 3-kinase (PI3K), which has been shown to play a significant role in synaptic plasticity in neurons and inflammation via microglia. This study shows that microglial PI3K is regulated epigenetically through histone modifications and posttranslationally through sumoylation and is involved in long-term potentiation (LTP) by modulating the expression of brain-derived neurotrophic factor (BDNF), which has been shown to be involved in neuronal synaptic plasticity. Sodium butyrate, a histone deacetylase inhibitor, upregulates PI3K expression, the phosphorylation of its downstream effectors, AKT and cAMP response element-binding protein (CREB), and the expression of BDNF in microglia, suggesting that BDNF secretion is regulated in microglia via epigenetic regulation of PI3K. Further, knockdown of SUMO1 in BV2 microglia results in a decrease in the expression of PI3K, the phosphorylation of AKT and CREB, as well as the expression of BDNF. These results suggest that microglial PI3K is epigenetically regulated by histone modifications and posttranslationally modified by sumoylation, leading to altered expression of BDNF. Whole-cell voltage-clamp showed the involvement of microglia in neuronal LTP, as selective ablation or disruption of microglia with clodronate in rat hippocampal slices abolished LTP. However, LTP was rescued when the same hippocampal slices were treated with active PI3K or BDNF, indicating that microglial PI3K/AKT signaling contributes to LTP and synaptic plasticity. Understanding the mechanisms by which microglial PI3K influences synapses provides insights into the ways it can modulate synaptic transmission and plasticity in learning and memory.

Biomimicking Fiber Platform with Tunable Stiffness to Study Mechanotransduction Reveals Stiffness Enhances Oligodendrocyte Differentiation but Impedes Myelination through YAP-Dependent Regulation.

A key hallmark of many diseases, especially those in the central nervous system (CNS), is the change in tissue stiffness due to inflammation and scarring. However, how such changes in microenvironment affect the regenerative process remains poorly understood. Here, a biomimicking fiber platform that provides independent variation of fiber structural and intrinsic stiffness is reported. To demonstrate the functionality of these constructs as a mechanotransduction study platform, these substrates are utilized as artificial axons and the effects of axon structural versus intrinsic stiffness on CNS myelination are independently analyzed. While studies have shown that substrate stiffness affects oligodendrocyte differentiation, the effects of mechanical stiffness on the final functional state of oligodendrocyte (i.e., myelination) has not been shown prior to this. Here, it is demonstrated that a stiff mechanical microenvironment impedes oligodendrocyte myelination, independently and distinctively from oligodendrocyte differentiation. Yes-associated protein is identified to be involved in influencing oligodendrocyte myelination through mechanotransduction. The opposing effects on oligodendrocyte differentiation and myelination provide important implications for current work screening for promyelinating drugs, since these efforts have focused mainly on promoting oligodendrocyte differentiation. Thus, the platform may have considerable utility as part of a drug discovery program in identifying molecules that promote both differentiation and myelination.

G9a/GLP Complex Acts as a Bidirectional Switch to Regulate Metabotropic Glutamate Receptor-Dependent Plasticity in Hippocampal CA1 Pyramidal Neurons.

Metabotropic glutamate receptor-dependent long-term depression (mGluR-LTD) is conventionally considered to be solely dependent on local protein synthesis. Given the impact of epigenetics on memory, the intriguing question is whether epigenetic regulation influences mGluR-LTD as well. G9a/GLP histone lysine methyltransferase complex is crucial for brain development and goal-directed learning as well as for drug-addiction. In this study, we analyzed whether the epigenetic regulation by G9a/GLP complex affects mGluR-LTD in CA1 hippocampal pyramidal neurons of 5-7 weeks old male Wistar rats. In hippocampal slices with intact CA1 dendritic regions, inhibition of G9a/GLP activity abolished mGluR-LTD. The inhibition of this complex upregulated the expression of plasticity proteins like PKMζ, which mediated the prevention of mGluR-LTD expression by regulating the NSF-GluA2-mediated trafficking of AMPA receptors towards the postsynaptic site. G9a/GLP inhibition during the induction of mGluR-LTD also downregulated the protein levels of phosphorylated-GluA2 and Arc. Interestingly, G9a/GLP inhibition could not impede the mGluR-LTD when the cell-body was severed. Our study highlights the role of G9a/GLP complex in intact neuronal network as a bidirectional switch; when turned on, it facilitates the expression of mGluR-LTD, and when turned off, it promotes the expression of long-term potentiation.

Metaplasticity mechanisms restore plasticity and associativity in an animal model of Alzheimer's disease.

Dynamic regulation of plasticity thresholds in a neuronal population is critical for the formation of long-term plasticity and memory and is achieved by mechanisms such as metaplasticity. Metaplasticity tunes the synapses to undergo changes that are necessary prerequisites for memory storage under physiological and pathological conditions. Here we discovered that, in amyloid precursor protein (APP)/presenilin-1 (PS1) mice (age 3-4 mo), a prominent mouse model of Alzheimer's disease (AD), late long-term potentiation (LTP; L-LTP) and its associative plasticity mechanisms such as synaptic tagging and capture (STC) were impaired already in presymptomatic mice. Interestingly, late long-term depression (LTD; L-LTD) was not compromised, but the positive associative interaction of LTP and LTD, cross-capture, was altered in these mice. Metaplastic activation of ryanodine receptors (RyRs) in these neurons reestablished L-LTP and STC. We propose that RyR-mediated metaplastic mechanisms can be considered as a possible therapeutic target for counteracting synaptic impairments in the neuronal networks during the early progression of AD.