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.

Porphyran Attenuates Neuronal Loss in the Hippocampal CA1 Subregion Induced by Ischemia and Reperfusion in Gerbils by Inhibiting NLRP3 Inflammasome-Mediated Neuroinflammation.

Porphyran, a sulfated polysaccharide found in various species of marine red algae, has been demonstrated to exhibit diverse bioactivities, including anti-inflammatory effects. However, the protective effects of porphyran against cerebral ischemia and reperfusion (IR) injury have not been investigated. The aim of this study was to examine the neuroprotective effects of porphyran against brain IR injury and its underlying mechanisms using a gerbil model of transient forebrain ischemia (IR in the forebrain), which results in pyramidal cell (principal neuron) loss in the cornu ammonis 1 (CA1) subregion of the hippocampus on day 4 after IR. Porphyran (25 and 50 mg/kg) was orally administered daily for one week prior to IR. Pretreatment with 50 mg/kg of porphyran, but not 25 mg/kg, significantly attenuated locomotor hyperactivity and protected pyramidal cells located in the CA1 area from IR injury. The pretreatment with 50 mg/kg of porphyran significantly suppressed the IR-induced activation and proliferation of microglia in the CA1 subregion. Additionally, the pretreatment significantly inhibited the overexpressions of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing protein-3 (NLRP3) inflammasome complex, and pro-inflammatory cytokines (interleukin 1 beta and interleukin 18) induced by IR in the CA1 subregion. Overall, our findings suggest that porphyran exerts neuroprotective effects against brain IR injury, potentially by reducing the reaction (activation) and proliferation of microglia and reducing NLRP3 inflammasome-mediated neuroinflammation.

Cannabidiol and positive effects on object recognition memory in an in vivo model of Fragile X Syndrome: Obligatory role of hippocampal GPR55 receptors.

Cannabidiol (CBD), a non-psychotomimetic constituent of Cannabis sativa, has been recently approved for epileptic syndromes often associated with Autism spectrum disorder (ASD). However, the putative efficacy and mechanism of action of CBD in patients suffering from ASD and related comorbidities remain debated, especially because of the complex pharmacology of CBD. We used pharmacological, immunohistochemical and biochemical approaches to investigate the effects and mechanisms of action of CBD in the recently validated Fmr1-Δexon 8 rat model of ASD, that is also a model of Fragile X Syndrome (FXS), the leading monogenic cause of autism. CBD rescued the cognitive deficits displayed by juvenile Fmr1-Δexon 8 animals, without inducing tolerance after repeated administration. Blockade of CA1 hippocampal GPR55 receptors prevented the beneficial effect of both CBD and the fatty acid amide hydrolase (FAAH) inhibitor URB597 in the short-term recognition memory deficits displayed by Fmr1-Δexon 8 rats. Thus, CBD may exert its beneficial effects through CA1 hippocampal GPR55 receptors. Docking analysis further confirmed that the mechanism of action of CBD might involve competition for brain fatty acid binding proteins (FABPs) that deliver anandamide and related bioactive lipids to their catabolic enzyme FAAH. These findings demonstrate that CBD reduced cognitive deficits in a rat model of FXS and provide initial mechanistic insights into its therapeutic potential in neurodevelopmental disorders.

Serotonin Signaling in Hippocampus during Initial Cocaine Abstinence Drives Persistent Drug Seeking.

The initiation of abstinence after chronic drug self-administration is stressful. Cocaine-seeking behavior on the first day of the absence of the expected drug (Extinction Day 1, ED1) is reduced by blocking 5-HT signaling in dorsal hippocampal cornu ammonis 1 (CA1) in both male and female rats. We hypothesized that the experience of ED1 can substantially influence later relapse behavior and that dorsal raphe (DR) serotonin (5-HT) input to CA1 may be involved. We inhibited 5-HT1A/1B receptors (WAY-100635 plus GR-127935), or DR input (chemogenetics), in CA1 on ED1 to test the role of this pathway on cocaine-seeking persistence 2 weeks later. We also inhibited 5-HT1A or 5-HT1B receptors in CA1 during conditioned place preference (CPP) for cocaine, to examine mechanisms involved in the persistent effects of ED1 manipulations. Inhibition of DR inputs, or 5-HT1A/1B signaling, in CA1 decreased drug seeking on ED1 and decreased cocaine seeking 2 weeks later revealing that 5-HT signaling in CA1 during ED1 contributes to persistent drug seeking during abstinence. In addition, 5-HT1B antagonism alone transiently decreased drug-associated memory performance when given prior to a CPP test, whereas similar antagonism of 5-HT1A alone had no such effect but blocked CPP retrieval on a test 24 h later. These CPP findings are consistent with prior work showing that DR inputs to CA1 augment recall of the drug-associated context and drug seeking via 5-HT1B receptors and prevent consolidation of the updated nondrug context via 5-HT1A receptors. Thus, treatments that modulate 5-HT-dependent memory mechanisms in CA1 during initial abstinence may facilitate later maintenance of abstinence.

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.

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.

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.

Effect of nootropic dipeptide noopept on CA1 pyramidal neurons involves α7AChRs on interneurons in hippocampal slices from rat.

Noopept (NP) is a proline-containing dipeptide with nootropic and neuroprotective properties. We have previously shown that NP significantly increased the frequency of spontaneous IPSCs in hippocampal CA1 pyramidal cells mediated by the activation of inhibitory interneurons in stratum radiatum. The cholinergic system plays an important role in the performance of cognitive functions, furthermore multiple behavioral and clinical facts link NP with the cholinergic system. The present study was undertaken to reveal the possible interaction of NP with neuronal nicotinic acetylcholine receptors (nAChRs). Currents were recorded from rat hippocampal neurons using the whole-cell, patch-clamp technique. NP (5 µM) increased the action potential firing frequency recorded from GABAergic interneurons in the stratum radiatum (SR) of CA1 region. This effect was almost completely abolished by the application of the α7 nAChR-selective antagonists α-bungarotoxin (α-BGT; 6 nM) and methyllycaconitine (MLA; 20 nM). The increase in the frequency of spontaneous IPSCs in CA1 pyramidal cells induced by NP was also eliminated by α7 nAChRs antagonists. These results imply the involvement of α7 nAChRs in the modulation of hippocampal neuronal activity caused by NP and indicate that a7 nAChRs are an important site of action of NP.

Intra-CA1 injection of orexin receptors antagonism attenuates the stress-induced analgesia in a rat acute pain model.

Orexins or hypocretins are excitatory neuropeptides predominantly produced by neuronal clusters in the lateral hypothalamus. The orexinergic system's involvement in pain modulation makes it a candidate for pain control alternative to the opioid system. Moreover, orexin-1 and orexin -2 receptors (OX1r and OX2r, respectively) play a role in responsiveness to stressful stimuli. Some evidence indicates that the Cornu Ammonis 1 (CA1) region of the hippocampus potentially participates in the modulation of both pain and stress. In quest of better understanding the interaction between orexin receptors and stress-induced analgesia (SIA), The present study examined the involvement of OX1r and OX2r within the CA1 in response to acute pain after exposure to forced swim stress (FSS) for a 6-min period. Adult male Wistar rats received different doses of OX1r antagonist (SB334867; 1, 3, 10, and 30 nmol), OX2r antagonist (TCS OX2 29; 3, 10, 30 and 100 nmol), or vehicle (0.5 µl DMSO) through an implanted cannula. After that, animals individually experienced acute pain by performing the tail-flick test. Results indicated that FSS produces antinociceptive responses in the tail-flick test. Blockade of both orexin receptors within the CA1 region attenuated the analgesic effect of FSS. The antinociceptive effect of swim stress was prevented by lower doses of SB334867 than TCS OX2 29. These findings show that the orexinergic system might be partially involved in the SIA via the OX1 and OX2 receptors in the hippocampal CA1 region.

DL-3-n-butylphthalide imparts neuroprotection via Nrf2/SIRT3 pathway in a mouse model of vascular dementia.

The goal of this study was to explore the mechanism of action of DL-3-n-butylphthalidein (NBP) the treatment of vascular dementia (VD) in mice. A vascular dementia mouse model was established with repeated cerebral ischemia/reperfusion (I/R), followed by administration of two different doses of NBP for 28 days. A Morris water maze was used to detect any changes in spatial cognition, while H&E staining was used to observe any histopathological changes in the hippocampus. The number of Caspase-3 and Caspase-9 positive neurons in the hippocampal CA1 region were also assessed using immunohistochemistry. The expression of Nrf2, Sirt3, and autophagy-related factors LC3 II/I and p62 in the hippocampus were detected by Western blotting. The results indicated that NBP treatment ameliorated learning and memory deficits, attenuated pathological damage in the CA1 regions, and reduced autophagy and apoptosis via the Nrf2/SIRT3 pathway after repeated cerebral I/R. Therefore, NBP treatment can improve the learning and cognitive memory of VD mice, possibly through the inhibition of autophagy and apoptosis mediated by the Nrf2/SIRT3 signaling pathway.

A hippocampus dependent neural circuit loop underlying the generation of auditory mismatch negativity.

Extracting relevant information and transforming it into appropriate behavior, is a fundamental brain function, and requires the coordination between the sensory and cognitive systems, however, the underlying mechanisms of interplay between sensory and cognition systems remain largely unknown. Here, we developed a mouse model for mimicking human auditory mismatch negativity (MMN), a well-characterized translational biomarker for schizophrenia, and an index of early auditory information processing. We found that a subanesthetic dose of ketamine decreased the amplitude of MMN in adult mice. Using pharmacological and chemogenetic approaches, we identified an auditory cortex-entorhinal cortex-hippocampus neural circuit loop that is required for the generation of MMN. In addition, we found that inhibition of dCA1→MEC circuit impaired the auditory related fear discrimination. Moreover, we found that ketamine induced MMN deficiency by inhibition of long-range GABAergic projection from the CA1 region of the dorsal hippocampus to the medial entorhinal cortex. These results provided circuit insights for ketamine effects and early auditory information processing. As the entorhinal cortex is the interface between the neocortex and hippocampus, and the hippocampus is critical for the formation, consolidation, and retrieval of episodic memories and other cognition, our results provide a neural mechanism for the interplay between the sensory and cognition systems.

Orexin receptors in the CA1 region of hippocampus modulate the stress-induced antinociceptive responses in an animal model of persistent inflammatory pain.

Stress activates multiple neural pathways and neurotransmitters that often suppress pain perception, the phenomenon called stress-induced analgesia (SIA). Orexin neurons from the lateral hypothalamus project to entire brain structures such as the hippocampus. The present study examined this hypothesis that orexinergic receptors in the CA1 region of the hippocampus may play a modulatory role in the development of SIA in formalin test as an animal model of persistent inflammatory pain. One hundred-two adult male Wistar rats were administered with intra-CA1 orexin-1 receptor (OX1r) antagonist, SB334867, at the doses of 3, 10, 30, and 100 nmol or TCS OX2 29 as orexin-2 receptor (OX2r) antagonist at the doses of 1, 3, 10, and 30 nmol. Five min later, rats were exposed to forced swim stress (FSS) for a 6-min period. Then, pain-related behaviors induced by formalin injection were measured at the 5-min blocks during a 60-min period of formalin test. The current study indicated that solely stress exposure elicits antinociception in the early and late phases of the formalin test. The FSS-induced analgesia was prevented by intra-CA1 administration of SB334867 or TCS OX2 29 during either phase of the formalin test. Moreover, the contribution of the OX2r in the mediation of analgesic effect of stress was more prominent than that of the OX1r during both phases of the formalin test. It is suggested that OX1r and OX2r in the CA1 region of the hippocampus are involved in stress-induced analgesia in the animal model of persistent inflammatory pain.

Ghrelin signaling in dCA1 suppresses neuronal excitability and impairs memory acquisition via PI3K/Akt/GSK-3ß cascades.

Ghrelin is a circulating peptide hormone that promotes feeding and regulates metabolism in humans and rodents. The action of ghrelin is mediated by the growth hormone secretagogue receptor type 1a (GHSR-1a) that is widely distributed in the brain, including the hippocampus. Studies have demonstrated the critical role of hippocampal ghrelin/GHS-R1a signaling in synaptic physiology and memory. However, those findings are controversial, and the mechanism underlying ghrelin modulation of learning and memory is uncertain. Here, we report that micro-infusion of ghrelin in the CA1 region of the dorsal hippocampus during training specifically impairs memory acquisition. The activation of GHS-R1a and the subsequent PI3K/Akt/GSK3ß signaling cascades are involved in this process. Moreover, we report that bath application of ghrelin suppresses the intrinsic excitability of dCA1 pyramidal neurons through activating GHS-R1a, and PI3K inhibitor LY294002 blocks ghrelin's effect. However, LY294002 fails to rescue ghrelin-induced LTP impairment. Our findings support an adverse effect of ghrelin-dependent activation of GHS-R1a on memory acquisition, and suggest that PI3K/Akt/GSK3ß signaling-dependent repression of neuronal intrinsic excitability is an important novel mechanism underlying memory inhibition of ghrelin in the hippocampus.

Neonatal NMDA blockade alters the LTP, LTD and cognitive functions in male and female Wistar rats.

There is compelling evidence that neonatal blockade of NMDA receptors by phencyclidine (PCP) is associated with cognitive impairment in adulthood but little is known about the effects of early life PCP treatment on synaptic function later in life. Here, we sought to determine whether early life exposure to PCP alters the electrophysiologic function of hippocampal CA1 neurons in adult rats. To this end, male and female Wistar rats received either saline or PCP (10 mg/kg) on postnatal days (PND) 7, 9, and 11, and then underwent separate behavioral and electrophysiology tests in adulthood. Neonatal PCP treatment did not alter basic synaptic transmission and had only a modest effect on frequency following (FF) capacity but significantly decreased the paired-pulse facilitation (PPF) in the Schaffer collateral (SC)-CA1 pathway. We found that PCP treatment significantly attenuated the long-term potentiation (LTP) and long-term depression (LTD) in CA1 neurons accompanied by pronounced alteration in complex response profile in adult rats. The electrophysiology data were comparable in male and female rats and reliably associated with impaired spatial reference and working memories in these animals. Overall, this study suggests that blockade of NMDA receptors during early life deteriorates the short-term and long-term synaptic plasticity and complex response profile of CA1 neurons in adulthood.

Convergence of distinct signaling pathways on synaptic scaling to trigger rapid antidepressant action.

Ketamine is a noncompetitive glutamatergic N-methyl-d-aspartate receptor (NMDAR) antagonist that exerts rapid antidepressant effects. Preclinical studies identify eukaryotic elongation factor 2 kinase (eEF2K) signaling as essential for the rapid antidepressant action of ketamine. Here, we combine genetic, electrophysiological, and pharmacological strategies to investigate the role of eEF2K in synaptic function and find that acute, but not chronic, inhibition of eEF2K activity induces rapid synaptic scaling in the hippocampus. Retinoic acid (RA) signaling also elicits a similar form of rapid synaptic scaling in the hippocampus, which we observe is independent of eEF2K functioni. The RA signaling pathway is not required for ketamine-mediated antidepressant action; however, direct activation of the retinoic acid receptor α (RARα) evokes rapid antidepressant action resembling ketamine. Our findings show that ketamine and RARα activation independently elicit a similar form of multiplicative synaptic scaling that is causal for rapid antidepressant action.

Prophylactic treatment of curcumin in a rat model of depression by attenuating hippocampal synaptic loss.

Curcumin is a polyphenol substance considered to be effective in the treatment of a number of neurodegenerative diseases. However, details regarding the exact mechanisms for the protective effects of curcumin in neuropsychiatric disorders, like depression, remain unknown. In the pathogenesis of major depressive disorder (MDD) it appears that dysregulation of oxidative stress and immune systems, particularly within the hippocampal region, may play a critical role. Here, we show that pre-treatment with curcumin (40 mg kg-1) alleviates depression-like behaviors in a LPS-induced rat model of depression, effects which were accompanied with suppression of oxidative stress and inflammation and an inhibition of neuronal apoptosis in the hippocampal CA1 region, and results from ultramicrostructure electrophysiological experiments revealed that the curcumin pre-treatment significantly prevented excessive synaptic loss and enhanced synaptic functioning in this LPS-induced rat model. In addition, curcumin attenuated the increases in levels of miR-146a-5p and decreases in the expression of p-ERK signaling that would normally occur within CA1 regions of these depressed rats. Taken together, these results demonstrated that curcumin exerts neuroprotective and antidepressant activities by suppressing oxidative stress, neural inflammation and their related effects upon synaptic dysregulation. One of the mechanisms for these beneficial effects of curcumin appears to involve the miR-146a-5p/ERK signaling pathway within the hippocampal CA1 region. These findings not only elucidated some of the mechanisms underlying the neuroprotective/antidepressant effects of curcumin, but also suggested a role of curcumin as a potential therapeutic strategy for depression.

Suppression of ventral hippocampal CA1 pyramidal neuronal activities enhances water intake.

Thirst is an important interoceptive response and drives water consumption. The hippocampus actively modulates food intake and energy metabolism, but direct evidence for the exact role of the hippocampus in modulating drinking behaviors is lacking. We observed decreased number of c-Fos-positive neurons in the ventral hippocampal CA1 (vCA1) after water restriction or hypertonic saline injection in rats. Suppressed vCA1 neuronal activities under the hypertonic state were further confirmed with in vivo electrophysiological recording, and the level of suppression paralleled both the duration and the total amount of water consumption. Chemogenetic inhibition of vCA1 pyramidal neurons increased water consumption in rats injected with both normal and hypertonic saline. These findings suggest that suppression of vCA1 pyramidal neuronal activities enhances water intake.

Sulbactam improves binding property and uptake capacity of glutamate transporter-1 and decreases glutamate concentration in the CA1 region of hippocampus of global brain ischemic rats.

Glutamate transporter-1 (GLT-1) removes most glutamate in the synaptic cleft. Sulbactam confers neuronal protection against ischemic insults in the hippocampal CA1 region accompanied by the upregulation of GLT-1 expression in rats. The present study further investigates the effect of sulbactam on the binding property and uptake capacity of GLT-1 for glutamate, and the change in extracellular glutamate concentration in the hippocampal CA1 region of rats with global brain ischemia. The binding property and uptake capacity of GLT-1 were measured using a radioligand binding and uptake assay, respectively, with L-3H-glutamate. The extracellular glutamate concentration was detected using microdialysis and high-performance liquid chromatography-mass spectrometry. Neuropathological evaluation was performed based on thionin staining. It was shown that sulbactam pre-treatment changed GLT-1 binding property, including increased Bmax and decreased Kd values, increased GLT-1 uptake capacity for glutamate, and inhibited the elevation of extracellular glutamate concentration in rats with global cerebral ischemia. These effects of sulbactam were accompanied by its neuronal protection on the hippocampal CA1 neurons against delayed neuronal death resulted from ischemic insult. Furthermore, administration of GLT-1 antisense oligodeoxynucleotides, which inhibited the expression of GLT-1, blocked the aforementioned sulbactam-related effects, which suggested that GLT-1 upregulation mediated the above effect although other mechanisms independent of the upregulation of GLT-1 expression could not be excluded. It could be concluded that sulbactam improves the binding property and uptake capacity of GLT-1 for glutamate and then reduces the glutamate concentration and excitotoxicity during global cerebral ischemia, which contributes to the neuroprotection of sulbactam against brain ischemia.

A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action.

Ketamine produces rapid antidepressant action in patients with major depression or treatment-resistant depression. Studies have identified brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), as necessary for the antidepressant effects and underlying ketamine-induced synaptic potentiation in the hippocampus. Here, we delete BDNF or TrkB in presynaptic CA3 or postsynaptic CA1 regions of the Schaffer collateral pathway to investigate the rapid antidepressant action of ketamine. The deletion of Bdnf in CA3 or CA1 blocks the ketamine-induced synaptic potentiation. In contrast, ablation of TrkB only in postsynaptic CA1 eliminates the ketamine-induced synaptic potentiation. We confirm BDNF-TrkB signaling in CA1 is required for ketamine's rapid behavioral action. Moreover, ketamine application elicits dynamin1-dependent TrkB activation and downstream signaling to trigger rapid synaptic effects. Taken together, these data demonstrate a requirement for BDNF-TrkB signaling in CA1 neurons in ketamine-induced synaptic potentiation and identify a specific synaptic locus in eliciting ketamine's rapid antidepressant effects.

Somatostatin contributes to long-term potentiation at excitatory synapses onto hippocampal somatostatinergic interneurons.

Somatostatin-expressing interneurons (SOM-INs) are a major subpopulation of GABAergic cells in CA1 hippocampus that receive excitation from pyramidal cells (PCs), and, in turn, provide feedback inhibition onto PC dendrites. Excitatory synapses onto SOM-INs show a Hebbian long-term potentiation (LTP) mediated by type 1a metabotropic glutamate receptors (mGluR1a) that is implicated in hippocampus-dependent learning. The neuropeptide somatostatin (SST) is also critical for hippocampal long-term synaptic plasticity, as well as learning and memory. SST effects on hippocampal PCs are well documented, but its actions on inhibitory interneurons remain largely undetermined. In the present work, we investigate the involvement of SST in long-term potentiation of CA1 SOM-IN excitatory synapses using pharmacological approaches targeting the somatostatinergic system and whole cell recordings in slices from transgenic mice expressing eYFP in SOM-INs. We report that application of exogenous SST14 induces long-term potentiation of excitatory postsynaptic potentials in SOM-INs via somatostatin type 1-5 receptors (SST1-5Rs) but does not affect synapses of PC or parvalbumin-expressing interneurons. Hebbian LTP in SOM-INs was prevented by inhibition of SSTRs and by depletion of SST by cysteamine treatment, suggesting a critical role of endogenous SST in LTP. LTP of SOM-IN excitatory synapses induced by SST14 was independent of NMDAR and mGluR1a, activity-dependent, and prevented by blocking GABAA receptor function. Our results indicate that endogenous SST may contribute to Hebbian LTP at excitatory synapses of SOM-INs by controlling GABAA inhibition, uncovering a novel role for SST in regulating long-term synaptic plasticity in somatostatinergic cells that may be important for hippocampus-dependent memory processes.