Deficits In Long-term Potentiation Research Articles

Cerebral endothelial 3-mercaptopyruvate sulfurtransferase improves ischemia-induced cognitive impairment via interacting with protein phosphatase 2A

The catalytic activity of 3-mercaptopyruvate (3MP) sulfurtransferase (MPST) converts 3MP to hydrogen sulfide (H2S). However, the regulatory mechanisms governing MPST and its impact on the brain remain largely unexplored. Our study reveals the neuroprotective role of endothelial MPST-generated H2S, regulated by protein phosphatase 2A (PP2A). Bioinformatics analysis and RNA sequencing demonstrated that endothelial PP2A is associated with neurodegenerative disease pathways. Cerebral ischemic mice exhibited significant inactivation of endothelial PP2A, evidenced by the reduction of PP2Acα in the brain endothelium. Mice with endothelium-specific null PP2A (PP2AEC-cKO) exhibited neuronal loss, cognitive dysfunction, and long-term potentiation deficits. Postnatal inactivation of endothelial PP2A also contributes to cognitive dysfunction and neuronal loss. However, regaining endothelial PP2A activity by overexpressing Ppp2ca rescued neuronal dysfunction. Mechanistically, PP2A deficiency is intricately linked to the MPST–H2S signaling pathway. A robust reduction in endothelial MPST-dependent H2S production followed PP2A deficiency. Exogenous H2S treatment and AAV-mediated overexpression of MPST in brain endothelial cells significantly mitigated neuronal dysfunction in PP2AEC-cKO mice. Furthermore, PP2A deficiency promotes an increase in calcium influx and calpain2 phosphorylation, subsequently leading to MPST degradation. The PP2A activator (FTY720) and MPST activator (3MP sodium) both remarkably restored endothelial MPST-dependent H2S production, subsequently rescuing ischemia-induced neurological deficits. In conclusion, our study demonstrates that endothelial PP2A deficiency leads to MPST degradation by activating calpain2, thus damaging neuronal function.

Pretreatment with tetramethylpyrazine alleviated the impairment of learning and memory induced by sevoflurane exposure in neonatal rats

Sevoflurane impairs learning and memory of the developing brain. However, strategies to mitigate these detrimental effects have been scarce. Herein, we investigated whether tetramethylpyrazine could alleviate the impairment of learning and memory and its underlying mechanisim in sevoflurane-exposed neonatal rats. Postnatal 7-day Sprague-Dawley (SD) rats or primary hippocampal neurons were pretreated with tetramethylpyrazine and then exposed to sevoflurane. The terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) and lactate dehydrogenase (LDH) assays were used to detect neuronal injury. Learning and memory function were evaluated by novel object recognition and Morris water maze tests. Long-term potentiation (LTP) was recorded to evaluate synaptic plasticity electrophysiologically in the hippocampal slices. Golgi-Cox staining or PSD95 immunochemistry was used to detect the morphology of dendritic spines. Western blotting was employed to assess the expressions of cleaved Caspase-3, PSD95, NMDAR1, NMDAR2A and NMDAR2B in the hippocampus or cultured neurons. It was found that neonatal exposure of sevoflurane impaired learning and memory, increased neuronal apoptosis, altered the morphology of dendritic spine, upregulated the expressions of NMDAR2A and PSD95, and induced LTP deficits. Pretreatment with tetramethylpyrazine not only alleviated impairment of learning and memory, but also improved sevoflurane-induced changes in neuronal damage, dendritic spine morphology, NMDAR2A and PSD95 expressions, as well as LTP. These findings indicated that pretreatment with tetramethylpyrazine alleviated the impairment of learning and memory induced by sevoflurane through improvement of hippocampal synaptic plasticity in neonatal rats.

The administration of a phentolamine infusion into the basolateral amygdala enhances long-term memory and diminishes anxiety-like behavior in stressed rats.

The basolateral amygdala (BLA) contains adrenergic receptors, which are known to be involved in stress, anxiety, and memory. The objective of this study was to explore whether inhibition of α-adrenergic receptors (by phentolamine, an α-adrenergic receptor antagonist) in the BLA can reduce foot-shock stress-induced anxiety-like behavior, memory deficits, and long-term potentiation (LTP) deficits within the CA1 region of the rat hippocampus. Forty male Wistar rats were assigned to the intact, control, stress (Str), Phent (phentolamine), and Phent + Str groups. Animals were subjected to six shocks on 4 consecutive days, and phentolamine was injected into BLA 20 min before the animals were placed in the foot-shock stress apparatus. Results from the elevated plus maze test (EPM) revealed a reduction in anxiety-like behaviors (by an increased number of entries into the open arm, percentage of time spent in the open arm, and rearing and freezing) among stressed animals upon receiving injections of phentolamine into the BLA. The open-field test results (increased rearing, grooming, and freezing behaviors) were consistent with the EPM test results. Phentolamine infusion into the BLA enhanced spatial memory, reducing errors in finding the target hole and decreasing latency time in the Barnes maze test for stress and nonstress conditions. Injecting phentolamine into the BLA on both sides effectively prevented LTP impairment in hippocampal CA1 neurons after being subjected to foot-shock stress. It has been suggested that phentolamine in the BLA can effectively improve anxiety-like behaviors and memory deficits induced by foot-shock stress.

Analysis of early effects of human APOE isoforms on Alzheimer’s disease and type III hyperlipoproteinemia pathways using knock-in rat models with humanized APP and APOE

APOE is a major genetic factor in late-onset Alzheimer’s disease (LOAD), with APOE4 increasing risk, APOE3 acting as neutral, and APOE2 offering protection. APOE also plays key role in lipid metabolism, affecting both peripheral and central systems, particularly in lipoprotein metabolism in triglyceride and cholesterol regulation. APOE2 is linked to Hyperlipoproteinemia type III (HLP), characterized by mixed hypercholesterolemia and hypertriglyceridemia due to impaired binding to Low-Density Lipoproteins receptors. To explore the impact of human APOE isoforms on LOAD and lipid metabolism, we developed Long-Evans rats with human APOE2, APOE3, or APOE4 in place of rat Apoe. These rats were crossed with those carrying a humanized App allele to express human Aβ, which is more aggregation-prone than rodent Aβ, enabling the study of human APOE-human Aβ interactions. In this study, we focused on 80-day-old adolescent rats to analyze early changes that may be associated with the later development of LOAD. We found that APOE2hAβ rats had the highest levels of APOE in serum and brain, with no significant transcriptional differences among isoforms, suggesting variations in protein translation or stability. Aβ43 levels were significantly higher in male APOE4hAβ rats compared to APOE2hAβ rats. However, no differences in Tau or phosphorylated Tau levels were observed across the APOE isoforms. Neuroinflammation analysis revealed lower levels of IL13, IL4 and IL5 in APOE2hAβ males compared to APOE4hAβ males. Neuronal transmission and plasticity tests using field Input-Output (I/O) and long-term potentiation (LTP) recordings showed increased excitability in all APOE-carrying rats, with LTP deficits in APOE2hAβand APOE4hAβ rats compared to ApoehAβ and APOE3hAβ rats. Additionally, a lipidomic analysis of 222 lipid molecular species in serum samples showed that APOE2hAβ rats displayed elevated triglycerides and cholesterol, making them a valuable model for studying HLP. These rats also exhibited elevated levels of phosphatidylglycerol, phosphatidylserine, phosphatidylethanolamine, sphingomyelin, and lysophosphatidylcholine. Minimal differences in lipid profiles between APOE3hAβ and APOE4hAβ rats reflect findings from mouse models. Future studies will include comprehensive lipidomic analyses in various CNS regions and at older ages to further validate these models and explore the effects of APOE isoforms on lipid metabolism in relation to AD pathology.

Impaired Hippocampal Long-Term Potentiation and Memory Deficits upon Haploinsufficiency of MDGA1 Can Be Rescued by Acute Administration of D-Cycloserine.

The maintenance of proper brain function relies heavily on the balance of excitatory and inhibitory neural circuits, governed in part by synaptic adhesion molecules. Among these, MDGA1 (MAM domain-containing glycosylphosphatidylinositol anchor 1) acts as a suppressor of synapse formation by interfering with Neuroligin-mediated interactions, crucial for maintaining the excitatory-inhibitory (E/I) balance. Mdga1-/- mice exhibit selectively enhanced inhibitory synapse formation in their hippocampal pyramidal neurons, leading to impaired hippocampal long-term potentiation (LTP) and hippocampus-dependent learning and memory function; however, it has not been fully investigated yet if the reduction in MDGA1 protein levels would alter brain function. Here, we examined the behavioral and synaptic consequences of reduced MDGA1 protein levels in Mdga1+/- mice. As observed in Mdga1-/- mice, Mdga1+/- mice exhibited significant deficits in hippocampus-dependent learning and memory tasks, such as the Morris water maze and contextual fear-conditioning tests, along with a significant deficit in the long-term potentiation (LTP) in hippocampal Schaffer collateral CA1 synapses. The acute administration of D-cycloserine, a co-agonist of NMDAR (N-methyl-d-aspartate receptor), significantly ameliorated memory impairments and restored LTP deficits specifically in Mdga1+/- mice, while having no such effect on Mdga1-/- mice. These results highlight the critical role of MDGA1 in regulating inhibitory synapse formation and maintaining the E/I balance for proper cognitive function. These findings may also suggest potential therapeutic strategies targeting the E/I imbalance to alleviate cognitive deficits associated with neuropsychiatric disorders.

Astroglial CD38 impairs hippocampal synaptic plasticity after global cerebral ischemia

Cardiac arrest-induced global cerebral ischemia (GCI) results in profound cognitive impairment in survivors. Our prior work demonstrated persistent disruption of long-term potentiation (LTP) in hippocampal CA1 neurons, correlating with learning and memory deficits in a rodent model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Delayed inhibition of the Ca2+-permeable TRPM2 ion channel restored LTP post-CA/CPR, yet the mechanisms upstream of TRPM2 activation remain elusive. This study investigates CD38 as a potential regulator of TRPM2, highlighting a novel target to reverse hippocampal synaptic plasticity deficits after ischemia. We observe elevated levels of CD38 in activated astrocytes in the CA1 region of the hippocampus 7 days following CA/CPR in both male and female mice. Delayed inhibition of CD38 reverses hippocampal synaptic plasticity impairments at subacute timepoints after CA/CPR, phenocopying TRPM2 restoration of LTP. Our previous findings demonstrated that TRPM2 inhibition reverses the CA/CPR-induced enhancement of GABAA receptor (GABAAR) clustering, which contribute to ongoing LTP deficits. We, therefore, assessed the effect of CD38 on GABAergic inhibitory potentiation and find that inhibition of CD38 reverses GABAAR clustering in a TRPM2-dependent manner. In this study, we identify astroglial CD38 as a potential target and upstream regulator of the TRPM2 channel, offering a promising approach to restore hippocampal synaptic plasticity impairments following GCI through modulation of GABAergic signaling.

The ketamine metabolite (2R,6R)-hydroxynorketamine rescues hippocampal mRNA translation, synaptic plasticity and memory in mouse models of Alzheimer's disease.

Impaired brain protein synthesis, synaptic plasticity, and memory are major hallmarks of Alzheimer's disease (AD). The ketamine metabolite (2R,6R)-hydroxynorketamine (HNK) has been shown to modulate protein synthesis, but its effects on memory in AD models remain elusive. We investigated the effects of HNK on hippocampal protein synthesis, long-term potentiation (LTP), and memory in AD mouse models. HNK activated extracellular signal-regulated kinase 1/2 (ERK1/2), mechanistic target of rapamycin (mTOR), and p70S6 kinase 1 (S6K1)/ribosomal protein S6 signaling pathways. Treatment with HNK rescued hippocampal LTP and memory deficits in amyloid-β oligomers (AβO)-infused mice in an ERK1/2-dependent manner. Treatment with HNK further corrected aberrant transcription, LTP and memory in aged APP/PS1 mice. Our findings demonstrate that HNK induces signaling and transcriptional responses that correct synaptic and memory deficits in AD mice. These results raise the prospect that HNK could serve as a therapeutic approach in AD. The ketamine metabolite HNK activates hippocampal ERK/mTOR/S6 signaling pathways. HNK corrects hippocampal synaptic and memory defects in two mouse models of AD. Rescue of synaptic and memory impairments by HNK depends on ERK signaling. HNK corrects aberrant transcriptional signatures in APP/PS1 mice.

Cage effects on synaptic plasticity and its modulation in a mouse model of fragile X syndrome.

Fragile X syndrome (FXS) is characterized by impairments in executive function including different types of learning and memory. Long-term potentiation (LTP), thought to underlie the formation of memories, has been studied in the Fmr1 mouse model of FXS. However, there have been many discrepancies in the literature with inconsistent use of littermate and non-littermate Fmr1 knockout (KO) and wild-type (WT) control mice. Here, the influence of the breeding strategy (cage effect) on short-term potentiation (STP), LTP, contextual fear conditioning (CFC), expression of N-methyl-d-aspartate receptor (NMDAR) subunits and the modulation of NMDARs, were examined. The largest deficits in STP, LTP and CFC were found in KO mice compared with non-littermate WT. However, the expression of NMDAR subunits was unchanged in this comparison. Rather, NMDAR subunit (GluN1, 2A, 2B) expression was sensitive to the cage effect, with decreased expression in both WT and KO littermates compared with non-littermates. Interestingly, an NMDAR-positive allosteric modulator, UBP714, was only effective in potentiating the induction of LTP in non-littermate KO mice and not the littermate KO mice. These results suggest that commonly studied phenotypes in Fmr1 KOs are sensitive to the cage effect and therefore the breeding strategy may contribute to discrepancies in the literature.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Developmental ethanol exposure produces deficits in long-term potentiation invivo that persist following postnatal choline supplementation.

Fetal alcohol spectrum disorder (FASD) is one of the leading causes of neurodevelopmental disorder for which there is a pressing need for an effective treatment. Recent studies have investigated the essential nutrient choline as a postnatal treatment option. Supplementation with choline has produced improvements in behavioral tasks related to learning and memory and reverted changes in methylation signature following third-trimester equivalent ethanol exposure. We examined whether there are related improvements in hippocampal synaptic plasticity invivo. Sprague-Dawley offspring were administered binge-levels of ethanol from postnatal day (PND) 4 to 9, then treated with choline chloride (100 mg/kg/day) from PND 10 to 30. Invivo electrophysiology was performed on male and female offspring from PND 55 to 70. Long-term potentiation (LTP) was induced in the medial perforant pathway of the dentate gyrus using a theta-burst stimulation (TBS) protocol, and field-evoked postsynaptic potentials (EPSPs) were evoked for 60 min following the conditioning stimulus. Developmental ethanol exposure caused long-lasting deficits in LTP of the slope of the evoked responses and in the amplitude of the population spike potentiation. Neither deficit was rescued by postnatal choline supplementation. In contrast to our prior findings that choline can improve hippocampal plasticity (Nutrients, 2022, 14, 2004), here we found that deficits in hippocampal synaptic plasticity due to developmental ethanol exposure persisted into adulthood despite adolescent choline supplementation. Future research should examine more subtle changes in synaptic plasticity to identify synaptic changes that mirror behavioral improvements.

A TrkB and TrkC partial agonist restores deficits in synaptic function and promotes activity-dependent synaptic and microglial transcriptomic changes in a late-stage Alzheimer's mouse model.

Tropomyosin related kinase B (TrkB) and C (TrkC) receptor signaling promotes synaptic plasticity and interacts with pathways affected by amyloid beta (Aβ) toxicity. Upregulating TrkB/C signaling could reduce Alzheimer's disease (AD)-related degenerative signaling, memory loss, and synaptic dysfunction. PTX-BD10-2 (BD10-2), a small molecule TrkB/C receptor partial agonist, was orally administered to aged London/Swedish-APP mutant mice (APPL/S) and wild-type controls. Effects on memory and hippocampal long-term potentiation (LTP) were assessed using electrophysiology, behavioral studies, immunoblotting, immunofluorescence staining, and RNA sequencing. In APPL/S mice, BD10-2 treatment improved memory and LTP deficits. This was accompanied by normalized phosphorylation of protein kinase B (Akt), calcium-calmodulin-dependent kinase II (CaMKII), and AMPA-type glutamate receptors containing the subunit GluA1; enhanced activity-dependent recruitment of synaptic proteins; and increased excitatory synapse number. BD10-2 also had potentially favorable effects on LTP-dependent complement pathway and synaptic gene transcription. BD10-2 prevented APPL/S/Aβ-associated memory and LTP deficits, reduced abnormalities in synapse-related signaling and activity-dependent transcription of synaptic genes, and bolstered transcriptional changes associated with microglial immune response. Small molecule modulation of tropomyosin related kinase B (TrkB) and C (TrkC) restores long-term potentiation (LTP) and behavior in an Alzheimer's disease (AD) model. Modulation of TrkB and TrkC regulates synaptic activity-dependent transcription. TrkB and TrkC receptors are candidate targets for translational therapeutics. Electrophysiology combined with transcriptomics elucidates synaptic restoration. LTP identifies neuron and microglia AD-relevant human-mouse co-expression modules.

The histamine H3 receptor inverse agonist SAR-152954 reverses deficits in long-term potentiation associated with moderate prenatal alcohol exposure

Prenatal alcohol exposure can have persistent effects on learning, memory, and synaptic plasticity. Previous work from our group demonstrated deficits in long-term potentiation (LTP) of excitatory synapses on dentate gyrus granule cells in adult offspring of rat dams that consumed moderate levels of alcohol during pregnancy. At present, there are no pharmacotherapeutic agents approved for these deficits. Prior work established that systemic administration of the histaminergic H3R inverse agonist ABT-239 reversed deficits in LTP observed following moderate PAE. The present study examines the effect of a second H3R inverse agonist, SAR-152954, on LTP deficits following moderate PAE. We demonstrate that systemic administration of 1 mg/kg of SAR-152954 reverses deficits in potentiation of field excitatory post-synaptic potentials (fEPSPs) in adult male rats exposed to moderate PAE. Time-frequency analyses of evoked responses revealed PAE-related reductions in power during the fEPSP, and increased power during later components of evoked responses which are associated with feedback circuitry that are typically not assessed with traditional amplitude-based measures. Both effects were reversed by SAR-152954. These findings provide further evidence that H3R inverse agonism is a potential therapeutic strategy to address deficits in synaptic plasticity associated with PAE.

The Intellectual Disability Risk Gene Kdm5b Regulates Long-Term Memory Consolidation in the Hippocampus.

The histone lysine demethylase KDM5B is implicated in recessive intellectual disability disorders, and heterozygous, protein-truncating variants in KDM5B are associated with reduced cognitive function in the population. The KDM5 family of lysine demethylases has developmental and homeostatic functions in the brain, some of which appear to be independent of lysine demethylase activity. To determine the functions of KDM5B in hippocampus-dependent learning and memory, we first studied male and female mice homozygous for a Kdm5b Δ ARID allele that lacks demethylase activity. Kdm5b Δ ARID/ Δ ARID mice exhibited hyperactivity and long-term memory deficits in hippocampus-dependent learning tasks. The expression of immediate early, activity-dependent genes was downregulated in these mice and hyperactivated upon a learning stimulus compared with wild-type (WT) mice. A number of other learning-associated genes were also significantly dysregulated in the Kdm5b Δ ARID/ Δ ARID hippocampus. Next, we knocked down Kdm5b specifically in the adult, WT mouse hippocampus with shRNA. Kdm5b knockdown resulted in spontaneous seizures, hyperactivity, and hippocampus-dependent long-term memory and long-term potentiation deficits. These findings identify KDM5B as a critical regulator of gene expression and synaptic plasticity in the adult hippocampus and suggest that at least some of the cognitive phenotypes associated with KDM5B gene variants are caused by direct effects on memory consolidation mechanisms.

TRPM2 and CaMKII Signaling Drives Excessive GABAergic Synaptic Inhibition Following Ischemia.

Excitotoxicity and the concurrent loss of inhibition are well-defined mechanisms driving acute elevation in excitatory/inhibitory (E/I) balance and neuronal cell death following an ischemic insult to the brain. Despite the high prevalence of long-term disability in survivors of global cerebral ischemia (GCI) as a consequence of cardiac arrest, it remains unclear whether E/I imbalance persists beyond the acute phase and negatively affects functional recovery. We previously demonstrated sustained impairment of long-term potentiation (LTP) in hippocampal CA1 neurons correlating with deficits in learning and memory tasks in a murine model of cardiac arrest/cardiopulmonary resuscitation (CA/CPR). Here, we use CA/CPR and an in vitro ischemia model to elucidate mechanisms by which E/I imbalance contributes to ongoing hippocampal dysfunction in male mice. We reveal increased postsynaptic GABAA receptor (GABAAR) clustering and function in the CA1 region of the hippocampus that reduces the E/I ratio. Importantly, reduced GABAAR clustering observed in the first 24 h rebounds to an elevation of GABAergic clustering by 3 d postischemia. This increase in GABAergic inhibition required activation of the Ca2+-permeable ion channel transient receptor potential melastatin-2 (TRPM2), previously implicated in persistent LTP and memory deficits following CA/CPR. Furthermore, we find Ca2+-signaling, likely downstream of TRPM2 activation, upregulates Ca2+/calmodulin-dependent protein kinase II (CaMKII) activity, thereby driving the elevation of postsynaptic inhibitory function. Thus, we propose a novel mechanism by which inhibitory synaptic strength is upregulated in the context of ischemia and identify TRPM2 and CaMKII as potential pharmacological targets to restore perturbed synaptic plasticity and ameliorate cognitive function.

MDGA2 Constrains Glutamatergic Inputs Selectively onto CA1 Pyramidal Neurons to Optimize Neural Circuits for Plasticity, Memory, and Social Behavior.

Synapse organizers are essential for the development, transmission, and plasticity of synapses. Acting as rare synapse suppressors, the MAM domain containing glycosylphosphatidylinositol anchor (MDGA) proteins contributes to synapse organization by inhibiting the formation of the synaptogenic neuroligin-neurexin complex. A previous analysis of MDGA2 mice lacking a single copy of Mdga2 revealed upregulated glutamatergic synapses and behaviors consistent with autism. However, MDGA2 is expressed in diverse cell types and is localized to both excitatory and inhibitory synapses. Differentiating the network versus cell-specific effects of MDGA2 loss-of-function requires a cell-type and brain region-selective strategy. To address this, we generated mice harboring a conditional knockout of Mdga2 restricted to CA1 pyramidal neurons. Here we report that MDGA2 suppresses the density and function of excitatory synapses selectively on pyramidal neurons in the mature hippocampus. Conditional deletion of Mdga2 in CA1 pyramidal neurons of adult mice upregulated miniature and spontaneous excitatory postsynaptic potentials, vesicular glutamate transporter 1 intensity, and neuronal excitability. These effects were limited to glutamatergic synapses as no changes were detected in miniature and spontaneous inhibitory postsynaptic potential properties or vesicular GABA transporter intensity. Functionally, evoked basal synaptic transmission and AMPAR receptor currents were enhanced at glutamatergic inputs. At a behavioral level, memory appeared to be compromised in Mdga2 cKO mice as both novel object recognition and contextual fear conditioning performance were impaired, consistent with deficits in long-term potentiation in the CA3-CA1 pathway. Social affiliation, a behavioral analog of social deficits in autism, was similarly compromised. These results demonstrate that MDGA2 confines the properties of excitatory synapses to CA1 neurons in mature hippocampal circuits, thereby optimizing this network for plasticity, cognition, and social behaviors.

Locally Synthetized 17-β-Estradiol Reverses Amyloid-β-42-Induced Hippocampal Long-Term Potentiation Deficits.

Amyloid beta 1-42 (Aβ42) aggregates acutely impair hippocampal long-term potentiation (LTP) of synaptic transmission, and 17β-estradiol is crucial for hippocampal LTP. We tested whether boosting the synthesis of neural-derived 17β-estradiol (nE2) saves hippocampal LTP by the neurotoxic action of Aβ42. Electrophysiological recordings were performed to measure dentate gyrus (DG) LTP in rat hippocampal slices. Using a pharmacological approach, we tested the ability of nE2 to counteract the LTP impairment caused by acute exposure to soluble Aβ42 aggregates. nE2 was found to be required for LTP in DG under physiological conditions. Blockade of steroid 5α-reductase with finasteride, by increasing nE2 synthesis from testosterone (T), completely recovered LTP in slices treated with soluble Aβ42 aggregates. Modulation of the glutamate N-methyl-D aspartate receptor (NMDAR) by memantine effectively rescued the LTP deficit observed in slices exposed to Aβ42, and memantine prevented LTP reduction observed under the blocking of nE2 synthesis. nE2 is able to counteract Aβ42-induced synaptic dysfunction. This effect depends on a rapid, non-genomic mechanism of action of nE2, which may share a common pathway with glutamate NMDAR signaling.

NTS-105 decreased cell death and preserved long-term potentiation in an in vitro model of moderate traumatic brain injury

Traumatic brain injury (TBI) is a major cause of hospitalization and death. To mitigate these human costs, the search for effective drugs to treat TBI continues. In the current study, we evaluated the efficacy of the novel neurosteroid, NTS-105, to reduce post-traumatic pathobiology in an in vitro model of moderate TBI that utilizes an organotypic hippocampal slice culture. NTS-105 inhibited activation of the androgen receptor and the mineralocorticoid receptor, partially activated the progesterone B receptor and was not active at the glucocorticoid receptor. Treatment with NTS-105 starting one hour after injury decreased post-traumatic cell death in a dose-dependent manner, with 10 nM NTS-105 being most effective. Post-traumatic administration of 10 nM NTS-105 also prevented deficits in long-term potentiation (LTP) without adversely affecting neuronal activity in naïve cultures. We propose that the high potency pleiotropic action of NTS-105 beneficial effects at multiple receptors (e.g. androgen, mineralocorticoid and progesterone) provides significant mechanistic advantages over native neurosteroids such as progesterone, which lacked clinical success for the treatment of TBI. Our results suggest that this pleiotropic pharmacology may be a promising strategy for the effective treatment of TBI, and future studies should test its efficacy in pre-clinical animal models of TBI.

Increasing NPYergic transmission in the hippocampus rescues aging-related deficits of long-term potentiation in the mouse dentate gyrus.

Loss of neuropeptide Y (NPY)-expressing interneurons in the hippocampus and decaying cholinergic neuromodulation are thought to contribute to impaired cognitive function during aging. However, the interaction of these two neuromodulatory systems in maintaining hippocampal synaptic plasticity during healthy aging has not been explored so far. Here we report profound sex differences in the Neuropeptide-Y (NPY) levels in the dorsal dentate gyrus (DG) with higher NPY concentrations in the male mice compared to their female counterparts and a reduction of NPY levels during aging specifically in males. This change in aged males is accompanied by a deficit in theta burst-induced long-term potentiation (LTP) in the medial perforant path-to-dorsal DG (MPP-DG) synapse, which can be rescued by enhancing cholinergic activation with the acetylcholine esterase blocker, physostigmine. Importantly, NPYergic transmission is required for this rescue of LTP. Moreover, exogenous NPY application alone is sufficient to recover LTP induction in aged male mice, even in the absence of the cholinergic stimulator. Together, our results suggest that in male mice NPYergic neurotransmission is a critical factor for maintaining dorsal DG LTP during aging.

Prenatal Cannabinoid Exposure Elicits Memory Deficits Associated with Reduced PSA-NCAM Expression, Altered Glutamatergic Signaling, and Adaptations in Hippocampal Synaptic Plasticity.

Cannabis is now one of the most commonly used illicit substances among pregnant women. This is particularly concerning since developmental exposure to cannabinoids can elicit enduring neurofunctional and cognitive alterations. This study investigates the mechanisms of learning and memory deficits resulting from prenatal cannabinoid exposure (PCE) in adolescent offspring. The synthetic cannabinoid agonist WIN55,212-2 was administered to pregnant rats, and a series of behavioral, electrophysiological, and immunochemical studies were performed to identify potential mechanisms of memory deficits in the adolescent offspring. Hippocampal-dependent memory deficits in adolescent PCE animals were associated with decreased long-term potentiation (LTP) and enhanced long-term depression (LTD) at hippocampal Schaffer collateral-CA1 synapses, as well as an imbalance between GluN2A- and GluN2B-mediated signaling. Moreover, PCE reduced gene and protein expression of neural cell adhesion molecule (NCAM) and polysialylated-NCAM (PSA-NCAM), which are critical for GluN2A and GluN2B signaling balance. Administration of exogenous PSA abrogated the LTP deficits observed in PCE animals, suggesting PSA mediated alterations in GluN2A- and GluN2B- signaling pathways may be responsible for the impaired hippocampal synaptic plasticity resulting from PCE. These findings enhance our current understanding of how PCE affects memory and how this process can be manipulated for future therapeutic purposes.

A Ketogenic Diet may Improve Cognitive Function in Rats with Temporal Lobe Epilepsy by Regulating Endoplasmic Reticulum Stress and Synaptic Plasticity.

A ketogenic diet (KD) is often used in the treatment of refractory epilepsy. Many studies have found that it also has a positive impact on cognitive comorbidities, but the specific mechanism remains unclear. In many disease models, endoplasmic reticulum stress (ERS) and synaptic plasticity is considered a new therapeutic target for improving cognitive impairment, and it has become a research focus in recent years. Recently, studies have found that a KD has a certain regulatory effect on both ERS and synaptic plasticity, but this result has not been confirmed in epilepsy. To investigate the effect of a KD on ERS and synaptic plasticity. In this study, a rat model of temporal lobe epilepsy (TLE) induced by lithium chloride-pilocarpine was used. After the model was successfully established, the rats in each group were fed a normal diet or a KD for 28 days, and the effect of a KD on the latency and seizure frequency of spontaneous recurrent seizures (SRSs) was observed via video monitoring. Subsequently, a Morris water maze was used to evaluate the spatial learning and memory abilities of the rats in each group; the ultrastructure of the ER and the synapses of the hippocampus were observed by transmission electron microscopy, and the dendritic spine density of the hippocampus was analysed by Golgi staining. Long-term potentiation (LTP) was used to detect the synaptic plasticity of the rats' hippocampi, and the expression of ERS-related proteins and synapse-related proteins was detected by Western blotting. A KD effectively reduced the frequency of SRSs in rats with TLE and improved their learning and memory impairment. Further investigations found that a KD inhibited the up-regulation of glucose-regulated protein 78, phospho-protein kinase-like ER kinase, phosphorylated α subunit of eukaryotic initiation factor 2, activating transcription factor 4 and C/EBP homologous protein expression in the hippocampi of rats with TLE and protected the ultrastructure of the neuronal ER, suggesting that a KD suppressed excessive ERS induced by epilepsy. Concurrently, we also found that a KD not only improved the synaptic ultrastructure and increased the density of dendritic spines in rats with TLE but also reversed the epilepsy-induced LTP deficit to some extent. More importantly, the expression of postsynaptic density protein 95, synaptotagmin-1 and synaptosomal-associated protein 25 in the hippocampi of rats with epilepsy was significantly increased after KD intervention. The study findings indicate that a KD improves learning and memory impairment in rats with epilepsy, possibly by regulating ERS and synaptic plasticity.

The effects of carvacrol and p-cymene on Aβ1-42 -induced long-term potentiation deficit in male rats.

Alzheimer's disease (AD) is the most common type of dementia in which oxidative stress plays an important role. In this disease, learning and memory and the cellular mechanism associated with it, long-term potentiation (LTP), are impaired. Considering the beneficial effects of carvacrol (CAR) and p-cymene against AD, their effect was assessed on in vivo hippocampal LTP in the perforant pathway (PP)-dentate gyrus (DG) pathway in an Aβ1-42 -induced rat model of AD. Male Wistar rats were randomly assigned to five groups: sham: intracerebroventricular (ICV) injection of phosphate-buffered saline, Aβ: ICV Aβ1-42 injections, Aβ + CAR (50 mg/kg), Aβ + p-cymene (50 mg/kg), and Aβ + CAR + p-cymene. Administration of CAR and p-cymene was done by gavage daily 4 weeks before and 4 weeks after the Aβ injection. The population spike (PS) amplitude and field excitatory postsynaptic potentials (fEPSP) slope were determined in DG against the applied stimulation to the PP. Aβ-treated rats exhibited impaired LTP induction in the PP-DG synapses, resulting in significant reduction in both fEPSP slope and PS amplitude compared to the sham animals. Aβ-treated rats consumed either CAR or p-cymene separately (but not their combination), and showed an enhancement in fEPSP slope and PS amplitude of the DG granular cells. These data indicate that CAR or p-cymene can ameliorate Aβ-associated changes in synaptic plasticity. Surprisingly, the combination of CAR and p-cymene did not yield the same effect, suggesting a potential interaction between the two substances.