Neurosteroids mediate and modulate the effects of pro-inflammatory stimulation and toll-like receptors on hippocampal plasticity and learning.

Pro-inflammatory changes contribute to multiple neuropsychiatric illnesses. Understanding how these changes are involved in illnesses and identifying strategies to alter inflammatory responses offer paths to potentially novel treatments. We previously found that acute pro-inflammatory stimulation with high (µg/ml) lipopolysaccharide (LPS) for 10-15 min dampens long-term potentiation (LTP) in the hippocampus and impairs learning. Effects of LPS involved non-canonical inflammasome signaling but were independent of toll-like receptor 4 (TLR4), a known LPS receptor. Low (ng/ml) LPS also inhibits LTP when administered for 2-4 h, and here we report that this LPS exposure requires TLR4. We also found that effects of low LPS on LTP involve the oxysterol, 25-hydroxycholesterol, akin to high LPS. Effects of high LPS on LTP are blocked by inhibiting synthesis of 5α-reduced neurosteroids, indicating that neurosteroids mediate LTP inhibition. 5α-Neurosteroids also have anti-inflammatory effects, and we found that exogenous allopregnanolone (AlloP), a key 5α-reduced steroid, prevented effects of low but not high LPS on LTP. We also found that activation of TLR2, TLR3 and TLR7 inhibited LTP and that AlloP prevented the effects of TLR2 and TLR7, but not TLR3. The enantiomer of AlloP, a steroid that has anti-inflammatory actions but low activity at GABAA receptors, prevented LTP inhibition by TLR2, TLR3 and TLR7. In vivo, both AlloP enantiomers prevented LPS-induced learning defects. These studies indicate that neurosteroids play complex roles in network effects of acute neuroinflammation and have potential importance for development of AlloP analogues as therapeutic agents.

Effects of (S)-3,4-DCPG, an mGlu8 receptor agonist, on hippocampal long-term potentiation at perforant pathway-dentate gyrus synapses in prenatal valproic acid-induced rat model of autism.

Autism spectrum disorder (ASD) is a pervasive neurodevelopmental condition characterized by social interaction deficits, communication impairments, repetitive behaviors, and sensory sensitivities. While the etiology of ASD is multifaceted, abnormalities in glutamatergic neurotransmission and synaptic plasticity have been implicated. This study investigated the role of metabotropic glutamate receptor 8 (mGlu8) in modulating long-term potentiation (LTP) in a rat model of ASD induced by prenatal valproic acid (VPA) exposure. To induce an animal model with autism-like characteristics, pregnant rats received an intraperitoneal injection of 500 mg/kg of sodium valproate (NaVPA) on embryonic day 12.5. High-frequency stimulation was applied to the perforant path-dentate gyrus (PP-DG) synapse to induce LTP, while the mGlu8 receptor agonist (S)-3,4-dicarboxyphenylglycine (DCPG) was administered into the DG. The results revealed that VPA-exposed rats exhibited reduced LTP compared to controls. DCPG had contrasting effects, inhibiting LTP in controls and enhancing it in VPA-exposed rats. Moreover, reduced social novelty preference index (SNPI) in VPA-exposed rats was reversed by intra-DG administration of S-3,4-DCPG. In conclusion, our study advances our understanding of the complex relationship between glutamatergic neurotransmission, synaptic plasticity, and VPA-induced autism model. The findings suggest that mGlu8 receptor dysfunction plays a role in the impaired synaptic plasticity seen in ASD.

Adiponectin rescues synaptic plasticity in the dentate gyrus of a mouse model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Rapidly reversible persistent long-term potentiation inhibition by patient-derived brain tau and amyloid ß proteins.

How the two pathognomonic proteins of Alzheimer's disease (AD); amyloid ß (Aß) and tau, cause synaptic failure remains enigmatic. Certain synthetic and recombinant forms of these proteins are known to act concurrently to acutely inhibit long-term potentiation (LTP). Here, we examined the effect of early amyloidosis on the acute disruptive action of synaptotoxic tau prepared from recombinant protein and tau in patient-derived aqueous brain extracts. We also explored the persistence of the inhibition of LTP by different synaptotoxic tau preparations. A single intracerebral injection of aggregates of recombinant human tau that had been prepared by either sonication of fibrils (SτAs) or disulfide bond formation (oTau) rapidly and persistently inhibited LTP in rat hippocampus. The threshold for the acute inhibitory effect of oTau was lowered in amyloid precursor protein (APP)-transgenic rats. A single injection of synaptotoxic tau-containing AD or Pick's disease brain extracts also inhibited LTP, for over two weeks. Remarkably, the persistent disruption of synaptic plasticity by patient-derived brain tau was rapidly reversed by a single intracerebral injection of different anti-tau monoclonal antibodies, including one directed to a specific human tau amino acid sequence. We conclude that patient-derived LTP-disrupting tau species persist in the brain for weeks, maintaining their neuroactivity often in concert with Aß. This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

Tributyrin reverses the deleterious effect of saturated fat on working memory and synaptic plasticity in juvenile mice: differential effects in males and females.

Short-chain fatty acids, such as butyric acid, derived from the intestinal fermentation of dietary fiber, have been proposed as a treatment for certain pathologies of the central nervous system. Our research group has shown that tributyrin (TB), a butyric acid prodrug, reverses deficits in spatial memory and modulates hippocampal synaptic plasticity. In the present work, diets enriched in either saturated (SOLF; Saturated OiL-enriched Food) or unsaturated (UOLF; Unsaturated OiL-enriched Food) fat were supplied during either 2 h or 8 weeks to 5-week-old male and female mice undergoing a treatment schedule with TB. After the dietary treatment, spatial learning and memory (SLM) was assessed in both the Y-maze and the eight-arm radial maze (RAM). Hippocampal expression of genes involved in glutamatergic transmission as well as synaptic plasticity (long-term potentiation -LTP- and long-term depression -LTD-) were also analyzed. Our results show that 2 h of SOLF intake impaired LTP as well as the performance in the Y-Maze in juvenile male mice whereas no effect was found in females. Moreover, TB reversed both effects in SLM and LTP in males. In the case of chronic intake, both SOLF and UOLF deteriorated SLM measured in the RAM in both sexes whereas TB only reversed LTP impairment induced by SOLF in male mice. These results suggest that TB may have a potentially beneficial influence on learning and memory processes, contingent upon the type of diet and the sex of the individuals.

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 low and high doses administration of lutein improves memory and synaptic plasticity impairment through different mechanisms in a rat model of vascular dementia.

BACKGROUND AND AIM: Vascular dementia (VD) is a common type of dementia. This study aimed to evaluate the effects of low and high doses of lutein administration in bilateral-carotid vessel occlusion (2VO) rats. EXPERIMENTAL PROCEDURE: The rats were divided into the following groups: the control, sham-, vehicle (2VO+V) groups, and two groups after 2VO were treated with lutein 0.5 (2VO+LUT-o.5) and 5mg/kg (2VO+LUT-5). The passive-avoidance and Morris water maze were performed to examine fear and spatial memory. The field-potential recording was used to investigate the properties of basal synaptic transmission (BST), paired-pulse ratio (PPR), as an index for measurement of neurotransmitter release, and long-term potentiation (LTP). The hippocampus was removed to evaluate hippocampal cells, volume, and MDA level. RESULT: Treatment with low and high doses improves spatial memory and LTP impairment in VD rats, but only the high dose restores the fear memory, hippocampal cell loss, and volume and MDA level. Interestingly, low-dose, but not high-dose, increased PPR. However, BST recovered only in the high-dose treated group. CONCLUSIONS: Treatment with a low dose might affect neurotransmitter release probability, but a high dose affects postsynaptic processes. It seems likely that low and high doses improve memory and LTP through different mechanisms.

Cholecystokinin B receptor agonists alleviates anterograde amnesia in cholecystokinin-deficient and aged Alzheimer's disease mice.

BACKGROUND: As one major symptom of Alzheimer's disease (AD), anterograde amnesia describes patients with an inability in new memory formation. The crucial role of the entorhinal cortex in forming new memories has been well established, and the neuropeptide cholecystokinin (CCK) is reported to be released from the entorhinal cortex to enable neocortical associated memory and long-term potentiation. Though several studies reveal that the entorhinal cortex and CCK are related to AD, it is less well studied. It is unclear whether CCK is a good biomarker or further a great drug candidate for AD. METHODS: mRNA expressions of CCK and CCK-B receptor (CCKBR) were examined in two mouse models, 3xTg AD and CCK knock-out (CCK-/-) mice. Animals' cognition was investigated with Morris water maze, novel object recognition test and neuroplasticity with in-vitro electrophysiological recording. Drugs were given intraperitoneally to animals to investigate the rescue effects on cognitive deficits, or applied to brain slices directly to explore the influence in inducement of long-term potentiation. RESULTS: Aged 3xTg AD mice exhibited reduced CCK mRNA expression in the entorhinal cortex but reduced CCKBR expression in the neocortex and hippocampus, and impaired cognition and neuroplasticity comparable with CCK-/- mice. Importantly, the animals displayed improved performance and enhanced long-term potentiation after the treatment of CCKBR agonists. CONCLUSIONS: Here we provide more evidence to support the role of CCK in learning and memory and its potential to treat AD. We elaborated on the rescue effect of a promising novel drug, HT-267, on aged 3xTg AD mice. Although the physiological etiology of CCK in AD still needs to be further investigated, this study sheds light on a potential pharmaceutical candidate for AD and dementia.

Recruitment of cortical silent responses by forskolin in the anterior cingulate cortex of adult mice.

Recent studies using different experimental approaches demonstrate that silent synapses may exist in the adult cortex including the sensory cortex and anterior cingulate cortex (ACC). The postsynaptic form of long-term potentiation (LTP) in the ACC recruits some of these silent synapses and the activity of calcium-stimulated adenylyl cyclases (ACs) is required for such recruitment. It is unknown if the chemical activation of ACs may recruit silent synapses. In this study, we found that activation of ACs contributed to synaptic potentiation in the ACC of adult mice. Forskolin, a selective activator of ACs, recruited silent responses in the ACC of adult mice. The recruitment was long-lasting. Interestingly, the effect of forskolin was not universal, some silent synapses did not undergo potentiation or recruitment. These findings suggest that these adult cortical synapses are not homogenous. The application of a selective calcium-permeable AMPA receptor inhibitor 1-naphthyl acetyl spermine (NASPM) reversed the potentiation and the recruitment of silent responses, indicating that the AMPA receptor is required. Our results strongly suggest that the AC-dependent postsynaptic AMPA receptor contributes to the recruitment of silent responses at cortical LTP.

The 5-HT7 receptor antagonist SB 269970 ameliorates maternal fluoxetine exposure-induced impairment of synaptic plasticity in the prefrontal cortex of the offspring female mice.

The use of a selective serotonin reuptake inhibitor fluoxetine in depression during pregnancy and the postpartum period might increase the risk of affective disorders and cognitive symptoms in progeny. In animal models, maternal exposure to fluoxetine throughout gestation and lactation negatively affects the behavior of the offspring. Little is known about the effects of maternal fluoxetine on synaptic transmission and plasticity in the offspring cerebral cortex. During pregnancy and lactation C57BL/6J mouse dams received fluoxetine (7.5 mg/kg/day) with drinking water. Female offspring mice received intraperitoneal injections of the selective 5-HT7 receptor antagonist SB 269970 (2.5 mg/kg) for 7 days. Whole-cell and field potential electrophysiological recordings were performed in the medial prefrontal cortex (mPFC) ex vivo brain slices. Perinatal exposure to fluoxetine resulted in decreased field potentials and impaired long-term potentiation (LTP) in layer II/III of the mPFC of female young adult offspring. Neither the intrinsic excitability nor spontaneous excitatory postsynaptic currents were altered in layer II/III mPFC pyramidal neurons. In mPFC slices obtained from fluoxetine-treated mice that were administered SB 269970 both field potentials and LTP magnitude were restored and did not differ from controls. Treatment of fluoxetine-exposed mice with a selective 5-HT7 receptor antagonist, SB 269970, normalizes synaptic transmission and restores the potential for plasticity in the mPFC of mice exposed in utero and postnatally to fluoxetine.

Preventive effect of propolis on cognitive decline in Alzheimer's disease model mice.

Brazilian green propolis (propolis) is a chemically complex resinous substance that is a potentially viable therapeutic agent for Alzheimer's disease. Herein, propolis induced a transient increase in intracellular Ca2+ concentration ([Ca2+]i) in Neuro-2A cells; moreover, propolis-induced [Ca2+]i elevations were suppressed prior to 24-h pretreatment with amyloid-ß. To reveal the effect of [Ca2+]i elevation on impaired cognition, we performed memory-related behavioral tasks in APP-KI mice relative to WT mice at 4 and 12 months of age. Propolis, at 300-1000 mg/kg/d for 8 wk, significantly ameliorated cognitive deficits in APP-KI mice at 4 months, but not at 12 months of age. Consistent with behavioral observations, injured hippocampal long-term potentiation was markedly ameliorated in APP-KI mice at 4 months of age following repeated propolis administration. In addition, repeated administration of propolis significantly activated intracellular calcium signaling pathway in the CA1 region of APP-KI mice. These results suggest a preventive effect of propolis on cognitive decline through the activation of intracellular calcium signaling pathways in CA1 region of AD mice model.

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

BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSION AND IMPLICATIONS: 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.

Repeated Morphine Exposure Alters Temporoamonic-CA1 Synaptic Plasticity in Male Rat Hippocampus.

In this study, the electrophysiological and biochemical consequences of repeated exposure to morphine in male rats on glutamatergic synaptic transmission, synaptic plasticity, the expression of GABA receptors and glutamate receptors at the temporoammonic-CA1 synapse along the longitudinal axis of the hippocampus (dorsal, intermediate, ventral, DH, IH, VH, respectively) were investigated. Slice electrophysiological methods, qRT-PCR, and western blotting techniques were used to characterize synaptic plasticity properties. We showed that repeated morphine exposure (RME) reduced excitatory synaptic transmission and ability for long-term potentiation (LTP) in the VH as well as eliminated the dorsoventral difference in paired-pulse responses. A decreased expression of NR2B subunit in the VH and an increased expression GABAA receptor of α1 and α5 subunits in the DH were observed following RME. Furthermore, RME did not affect the expression of NR2A, AMPA receptor subunits, and γ2GABAA and GABAB receptors in either segment of the hippocampus. In sum, the impact of morphine may differ depending on the region of the hippocampus studied. A distinct change in the short- and long-term synaptic plasticity along the hippocampus long axis due to repeated morphine exposure, partially mediated by a change in the expression profile of glutamatergic receptor subunits. These findings can be useful in further understanding the cellular mechanism underlying deficits in information storage and, more generally, cognitive processes resulting from chronic opioid abuse.

Tenuifolin improves learning and memory by regulating long-term potentiation and dendritic structure of hippocampal CA1 area in healthy female mice but not male mice.

Polygala tenuifolia Wild is an ancient traditional Chinese medicine. Its main component, tenuifolin (TEN), has been proven to improve cognitive impairment caused by neurodegenerative diseases and ovariectomy. However, there was hardly any pharmacological research about TEN and its potential gender differences. Considering the reduction of TEN on learning and memory dysfunction in ovariectomized animals, therefore, we focused on the impact of TEN in different mice genders in the current study. Spontaneous alternation behavior (SAB), light-dark discrimination, and Morris water maze (MWM) tests were used to evaluate the mice's learning and memory abilities. The field excitatory postsynaptic potential (fEPSP) of the hippocampal CA1 region was recorded using an electrophysiological method, and the morphology of the dendritic structure was examined using Golgi staining. In the behavioral experiments, TEN improved the correct rate in female mice in the SAB test, the correct rate in the light-dark discrimination test, and the number of crossing platforms in the MWM test. Additionally, TEN reduced the latency of female mice rather than male mice in light-dark discrimination and MWM tests. Moreover, TEN could significantly increase the slope of fEPSP in hippocampal Schaffer-CA1 and enhance the total length and the number of intersections of dendrites in the hippocampal CA1 area in female mice but not in male mice. Collectively, the results of the current study showed that TEN improved learning and memory by regulating long-term potentiation (LTP) and dendritic structure of hippocampal CA1 area in female mice but not in males. These findings would help to explore the improvement mechanism of TEN on cognition and expand the knowledge of the potential therapeutic value of TEN in the treatment of cognitive impairment.

Targeting metaplasticity mechanisms to promote sustained antidepressant actions.

The discovery that subanesthetic doses of (R, S)-ketamine (ketamine) and (S)-ketamine (esketamine) rapidly induce antidepressant effects and promote sustained actions following drug clearance in depressed patients who are treatment-resistant to other therapies has resulted in a paradigm shift in the conceptualization of how rapidly and effectively depression can be treated. Consequently, the mechanism(s) that next generation antidepressants may engage to improve pathophysiology and resultant symptomology are being reconceptualized. Impaired excitatory glutamatergic synapses in mood-regulating circuits are likely a substantial contributor to the pathophysiology of depression. Metaplasticity is the process of regulating future capacity for plasticity by priming neurons with a stimulation that alters later neuronal plasticity responses. Accordingly, the development of treatment modalities that specifically modulate the duration, direction, or magnitude of glutamatergic synaptic plasticity events such as long-term potentiation (LTP), defined here as metaplastogens, may be an effective approach to reverse the pathophysiology underlying depression and improve depression symptoms. We review evidence that the initiating mechanisms of pharmacologically diverse rapid-acting antidepressants (i.e., ketamine mimetics) converge on consistent downstream molecular mediators that facilitate the expression/maintenance of increased synaptic strength and resultant persisting antidepressant effects. Specifically, while the initiating mechanisms of these therapies may differ (e.g., cell type-specificity, N-methyl-D-aspartate receptor (NMDAR) subtype-selective inhibition vs activation, metabotropic glutamate receptor 2/3 antagonism, AMPA receptor potentiation, 5-HT receptor-activating psychedelics, etc.), the sustained therapeutic mechanisms of putative rapid-acting antidepressants will be mediated, in part, by metaplastic effects that converge on consistent molecular mediators to enhance excitatory neurotransmission and altered capacity for synaptic plasticity. We conclude that the convergence of these therapeutic mechanisms provides the opportunity for metaplasticity processes to be harnessed as a druggable plasticity mechanism by next-generation therapeutics. Further, targeting metaplastic mechanisms presents therapeutic advantages including decreased dosing frequency and associated diminished adverse responses by eliminating the requirement for the drug to be continuously present.

Octadecaneuropeptide Ameliorates Cognitive Impairments Through Inhibiting Oxidative Stress in Alzheimer's Disease Models.

BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder characterized by amyloid-ß peptide (Aß) deposition. Aß accumulation induces oxidative stress, leading to mitochondrial dysfunction, apoptosis, and so forth. Octadecaneuropeptide (ODN), a diazepam-binding inhibitor (DBI)-derived peptide, has been reported to have antioxidant properties. However, it is unclear whether ODN has neuroprotective effects in AD. OBJECTIVE: To profile the potential effects of ODN on AD. METHODS: We established a mouse model of AD via microinjection of Aß in the lateral ventricle. Utilizing a combination of western blotting assays, electrophysiological recordings, and behavioral tests, we investigated the neuroprotective effects of ODN on AD. RESULTS: DBI expression was decreased in AD model mice and cells. Meanwhile, ODN decreased Aß generation by downregulating amyloidogenic AßPP processing in HEK-293 cells stably expressing human Swedish mutant APP695 and BACE1 (2EB2). Moreover, ODN could inhibit Aß-induced oxidative stress in primary cultured cells and mice, as reflected by a dramatic increase in antioxidants and a decrease in pro-oxidants. We also found that ODN could reduce oxidative stress-induced apoptosis by restoring mitochondrial membrane potential, intracellular Ca2+ and cleaved caspase-3 levels in Aß-treated primary cultured cells and mice. More importantly, intracerebroventricular injection of ODN attenuated cognitive impairments as well as long-term potentiation in Aß-treated mice. CONCLUSION: These results suggest that ODN may exert a potent neuroprotective effect against Aß-induced neurotoxicity and memory decline via its antioxidant effects, indicating that ODN may be a potential therapeutic agent for AD.

Age-Dependent and Pathway-Specific Bimodal Action of Nicotine on Synaptic Plasticity in the Hippocampus of Mice Lacking the miR-132/212 Genes.

Nicotine addiction develops predominantly during human adolescence through smoking. Self-administration experiments in rodents verify this biological preponderance to adolescence, suggesting evolutionary-conserved and age-defined mechanisms which influence the susceptibility to nicotine addiction. The hippocampus, a brain region linked to drug-related memory storage, undergoes major morpho-functional restructuring during adolescence and is strongly affected by nicotine stimulation. However, the signaling mechanisms shaping the effects of nicotine in young vs. adult brains remain unclear. MicroRNAs (miRNAs) emerged recently as modulators of brain neuroplasticity, learning and memory, and addiction. Nevertheless, the age-dependent interplay between miRNAs regulation and hippocampal nicotinergic signaling remains poorly explored. We here combined biophysical and pharmacological methods to examine the impact of miRNA-132/212 gene-deletion (miRNA-132/212-/-) and nicotine stimulation on synaptic functions in adolescent and mature adult mice at two hippocampal synaptic circuits: the medial perforant pathway (MPP) to dentate yrus (DG) synapses (MPP-DG) and CA3 Schaffer collaterals to CA1 synapses (CA3-CA1). Basal synaptic transmission and short-term (paired-pulse-induced) synaptic plasticity was unaltered in adolescent and adult miRNA-132/212-/- mice hippocampi, compared with wild-type controls. However, nicotine stimulation promoted CA3-CA1 synaptic potentiation in mature adult (not adolescent) wild-type and suppressed MPP-DG synaptic potentiation in miRNA-132/212-/- mice. Altered levels of CREB, Phospho-CREB, and acetylcholinesterase (AChE) expression were further detected in adult miRNA-132/212-/- mice hippocampi. These observations propose miRNAs as age-sensitive bimodal regulators of hippocampal nicotinergic signaling and, given the relevance of the hippocampus for drug-related memory storage, encourage further research on the influence of miRNAs 132 and 212 in nicotine addiction in the young and the adult brain.

Propofol improves learning and memory in post-traumatic stress disorder (PTSD) mice via recovering hippocampus synaptic plasticity.

AIMS: Propofol, the most commonly used intravenous anesthetic, is known for its protective effect in various human and animal disease models such as post-traumatic stress disease (PTSD). However, it still needs efforts to clarify the effect of propofol on fear memory extinction and the relevant mechanisms. METHODS: Fear memory extinction was examined in PTSD mice model. Thirty-six mice were randomly divided into three groups: a shock + propofol group (sh + Pro), shock + normal saline group (sh + NS), and sham group. The mice were treated with propofol (150 mg/kg) or normal saline (of the same volume) intraperitoneally 30 min after the conditioning. These mice's behavior was analysed with contextual test, sucrose preference test (SPT) and Morris water maze (MWM). Additionally, the synaptic plasticity of the hippocampus was examined by long-term potentiation (LTP) and long-term depression (LTD). KEY FINDINGS: Compared with the sham group, the sh + NS group showed increased freezing time and depressive behavior, meanwhile the sh + Pro group showed minor behavioral changes. What's more, we found that propofol rescued the impaired long-term potentiation (LTP) and long-term depression (LTD) in hippocampus of PTSD mice. All these suggest that propofol can accelerate fear memory extinction and change synaptic plasticity of PTSD mice. SIGNIFICANCE: The study proved that propofol can protect the mice from PTSD by reserving synaptic plasticity and brought a new insight into PTSD treatment indicating that propofol maybe a potential cure for PTSD.

Role of extracellular signal-regulated kinase in rubrofusarin-enhanced cognitive functions and neurite outgrowth.

Memory-enhancing agents have long been required for various reasons such as for obtaining a good score in a test in the young and for retaining memory in the aged. Although many studies have found that several natural products may be good candidates for memory enhancement, there is still a need for better agents. The present study investigated whether rubrofusarin, an active ingredient in Cassiae semen, enhances learning and memory in normal mice. Passive avoidance and Morris water maze tests were performed to determine the memory-enhancing ability of rubrofusarin. To investigate synaptic function, hippocampal long-term potentiation (LTP) was measured. Western blotting was performed to determine protein levels. To investigate neurite outgrowth, DCX immunohistochemistry and cell culture were utilised. Rubrofusarin (1, 3, 10, 30 mg/kg) enhanced memory in passive avoidance and Morris water maze tests. Moreover, rubrofusarin ameliorated scopolamine-induced memory impairment. In the rubrofusarin-treated group, high-frequency stimulation induced higher LTP in the hippocampal Schaffer-collateral pathway compared to the control group. The rubrofusarin-treated group showed a higher number of DCX-positive immature neurons with an increase in the length of dendrites compared to the control group in the hippocampal dentate gyrus region. In vitro experiments showed that rubrofusarin facilitated neurite outgrowth in neuro2a cells through extracellular signal-regulated kinase (ERK). Finally, we found that extracellular signal-regulated kinase (ERK) is required for rubrofusarin-induced enhancement of neurite outgrowth, learning and memory. These results demonstrate that rubrofusarin enhances learning and memory and neurite outgrowth, and these might need activation of ERK pathway.

Designed Peptide Inhibitors of STEP Phosphatase-GluA2 AMPA Receptor Interaction Enhance the Cognitive Performance in Rats.

Cognitive impairment and learning ability of the brain are directly linked to synaptic plasticity as measured in changes of long-term potentiation (LTP) and long-term depression (LTD) in animal models of brain diseases. LTD reflects a sustained reduction of the synaptic AMPA receptor content based on targeted clathrin-mediated endocytosis. AMPA receptor endocytosis is initiated by dephosphorylation of Tyr876 on the C-terminus of the AMPAR subunit GluA2. The brain-specific striatal-enriched protein tyrosine phosphatase (STEP) is responsible for this process. To identify new, highly effective inhibitors of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) internalization, we performed structure-based design of peptides able to inhibit STEP-GluA2-CT complex formation. Two short peptide derivatives were found as efficient in vitro inhibitors. Our in vivo experiments evidenced that both peptides restore the memory deficits and display anxiolytic and antidepressant effects in a scopolamine-treated rat model. The interference peptides identified and characterized here represent promising lead compounds for novel cognitive enhancers and/or behavioral modulators.