Hippocampal CA3-CA1 Synapses Research Articles

Wnt-5a Signaling Mediates Metaplasticity at Hippocampal CA3-CA1 Synapses in Mice.

Wnt signaling plays a role in synaptic plasticity, but the specific cellular events and molecular components involved in Wnt signaling-mediated synaptic plasticity are not well defined. Here, we report a change in the threshold required to induce synaptic plasticity that facilitates the induction of long-term potentiation (LTP) and inhibits the induction of long-term depression (LTD) during brief exposure to the noncanonical ligand Wnt-5a. Both effects are related to the metaplastic switch of hippocampal CA3-CA1 synaptic transmission, a complex mechanism underlying the regulation of the threshold required to induce synaptic plasticity and of synaptic efficacy. We observed an early increase in the amplitude of field excitatory postsynaptic potentials (fEPSPs) that persisted over time, including after washout. The first phase involves an increase in the fEPSP amplitude that is required to trigger a spontaneous second phase that depends on Jun N-terminal kinase (JNK) and N-methyl D-aspartate receptor (NMDAR) activity. These changes are prevented by treatment with secreted frizzled-related protein 2 (sFRP-2), an endogenous antagonist of Wnt ligands. Here, we demonstrate the contribution of Wnt-5a signaling to a process associated with metaplasticity at CA3-CA1 synapses that favors LTP over LTD.

Evolution of Glutamate Metabolism via GLUD2 Enhances Lactate-Dependent Synaptic Plasticity and Complex Cognition.

Human evolution is characterized by rapid brain enlargement and the emergence of unique cognitive abilities. Besides its distinctive cytoarchitectural organization and extensive inter-neuronal connectivity, the human brain is also defined by high rates of synaptic, mainly glutamatergic, transmission, and energy utilization. While these adaptations' origins remain elusive, evolutionary changes occurred in synaptic glutamate metabolism in the common ancestor of humans and apes via the emergence of GLUD2, a gene encoding the human glutamate dehydrogenase 2 (hGDH2) isoenzyme. Driven by positive selection, hGDH2 became adapted to function upon intense excitatory firing, a process central to the long-term strengthening of synaptic connections. It also gained expression in brain astrocytes and cortical pyramidal neurons, including the CA1-CA3 hippocampal cells, neurons crucial to cognition. In mice transgenic for GLUD2, theta-burst-evoked long-term potentiation (LTP) is markedly enhanced in hippocampal CA3-CA1 synapses, with patch-clamp recordings from CA1 pyramidal neurons revealing increased sNMDA receptor currents. D-lactate blocked LTP enhancement, implying that glutamate metabolism via hGDH2 potentiates L-lactate-dependent glia-neuron interaction, a process essential to memory consolidation. The transgenic (Tg) mice exhibited increased dendritic spine density/synaptogenesis in the hippocampus and improved complex cognitive functions. Hence, enhancement of neuron-glia communication, via GLUD2 evolution, likely contributed to human cognitive advancement by potentiating synaptic plasticity and inter-neuronal connectivity.

“Time windows” for switching kinase-phosphatase balance during inhibition of long-term potentialization of hippocampal synapses by amyloid aggregates

Phosphorylation and dephosphorylation of target proteins are crucial mechanisms for regulating cellular functions. These processes are mediated by protein kinases and phosphatases, respectively. Changes in the kinase-phosphatase balance, known as K-P balance, are well documented during the progression of amyloidosis. The overactivation of kinases or the failed activity of phosphatases is the root cause of hyperphosphorylation of the structural tau protein leading to the formation of fibrillar tangles. The data suggests bidirectional regulation of phosphorylation/dephosphorylation processes during amyloidosis-related states is consistent across different animal models and many protocols. Therefore, it is crucial to identify the “time windows” during which the K-P balance can be altered. Field excitatory postsynaptic potentials (fEPSPs) were recorded from the stratum radiatum located in area CA1. Baseline synaptic responses were generated by paired-pulse stimulation of the Schaffer collaterals at a frequency of 0.033 Hz using a bipolar electrode. Four 100 Hz trains were delivered 5 minutes apart to induce long-term potentiation (LTP). Serine and threonine phosphatase activity was assessed using a non-radioactive molybdate dye-based assay kit (Promega, USA) based on the manufacturer’s instructions. The procedure relies on the creation of a colored complex of phosphates with a dye containing molybdenum, followed by the measurement of optical densities of supernatants that were incubated against a control at 640 nm. The activity of protein kinase C (PKC) will be measured directly via an enzyme immunoassay (ELISA) on a plate reader, using a commercial Abcam kit (Abcam, USA). The technique relies on the binding of engineered antibodies to activated PKC, and optical densities of incubated supernatants are measured against a control at 450 nm. In this study, we identified two important time periods during the application of amyloid Aβ25-35 aggregates that affect plasticity in the CA3-CA1 synapses. Specifically, the PKC isoforms are activated during early neurochemical events (0–20 min of incubation of slices in the presence of Aβ25–35 aggregates). If the hippocampal CA3-CA1 synapses are tetanized during this period, we did not observe any inhibition of synaptic plasticity either in the early or late phase development of LTP. Biochemical analysis indicates that hippocampal slices pretreated with Aβ25–35 aggregates for 20–30 minutes exhibit increased PKC activity, whereas no such effect is observed after one hour of incubation. Simultaneously, the hour-long incubation of hippocampal slices in the presence of Aβ25–35 aggregates resulted in the disappearance of long-term potentiation and the return of responses to the pre-tetanic level of synaptic transmission during the late-LTP phase (3 hours after tetanus induction). Inhibitory analysis revealed that an abrupt rise in the activity of stress-induced phosphatase 1α (PP1α) interrupts kinase-mediated signals after LTP induction, leading to the suppression of fEPSPs in the CA3-CA1 synapses. These findings suggest that exposing hippocampal slices to Aβ25–35 aggregates for 20–30 minutes may alter the K-P balance and enhance kinase activity through PKC isoform induction. The majority of PKC isoforms exhibit a tendency to desensitize following activation. Probably, the depletion of the pool of PKCs, which occurs within the first 20–30 minutes after incubation of hippocampal slices with Aβ25–35 aggregates, along with a notable elevation in the activity of stress-induced phosphatase PP1α, is accountable for the second time window for switching the kinase-phosphatase balance, stabilized after an hour of incubation of hippocampal slices in the presence of Aβ25–35 aggregates. Incubating hippocampal slices with Aβ25–35 aggregates (for 0–30 minutes) leads to a shift in the kinase-phosphatase balance towards the activity of kinases due to the activation of PKC isoforms. After this stage, there is a significant rise in phosphatase activity, resulting from the induction of PP1α. This induces a shift in the balance between kinase and phosphatase towards dephosphorylation processes.

Age-dependent Effects of Dopamine on Working Memory and Synaptic Plasticity in Hippocampal CA3-CA1 Synapses in Mice.

Normal aging in mammals is accompanied by a decline in learning and memory. Dopamine plays a vital role in regulating cognitive functions, but it declines with age: During non-pathological aging, dopamine levels, receptors, and transporters decrease. Regarding the role of the dopaminergic system's changes in old age, we examined the effect of age and applied dopamine on working memory, synaptic transmission, and long-term potentiation (LTP) induction and maintenance in young adult and mature adult mice. We employed the Y-maze spontaneous alteration test to evaluate working memory. Maturation had no observed effect on working memory performance. Interestingly, working memory performance increased following intracerebroventricular administration of dopamine only in mature adult mice. We employed evoked field potential recording (in vitro) to assess the effects of age and maturation on the long-term potentiation (LTP) induction and maintenance. There was no difference in LTP induction and maintenance between young and mature adult mice before dopamine application. However, the application of dopamine on mature adult murine slices increased LTP magnitude compared to slices from young adults. According to the obtained results, it may be concluded that hippocampal neural excitability increased in mature adult subjects, and application of dopamine abolished the difference in neural excitability among young mature and adult mature groups; which was accompanied with increment of working memory and synaptic potentiation in mature adult animals.

Time-course adaptive changes in hippocampal transcriptome and synaptic function induced by simulated microgravity associated with cognition.

The investigation of cognitive function in microgravity, both short-term and long-term, remains largely descriptive. And the underlying mechanisms of the changes over time remain unclear. Behavioral tests, electrophysiological recording, and RNA sequencing were used to observe differences in behavior, synaptic plasticity, and gene expression. Initially, we measured the performance of spatial cognition exposed to long-term simulated microgravity (SM). Both working memory and advanced cognitive abilities were enhanced. Somewhat surprisingly, the synaptic plasticity of the hippocampal CA3-CA1 synapse was impaired. To gain insight into the mechanism of changing regularity over time, transcriptome sequencing in the hippocampus was performed. The analysis identified 20 differentially expressed genes (DEGs) in the hippocampus after short-term modeling, 19 of which were up-regulated. Gene Ontology (GO) analysis showed that these up-regulated genes were mainly enriched in synaptic-related processes, such as Stxbp5l and Epha6. This might be related to the enhancement of working memory performance under short-term SM exposure. Under exposure to long-term SM, 7 DEGs were identified in the hippocampus, all of which were up-regulated and related to oxidative stress and metabolism, such as Depp1 and Lrg1. Compensatory effects occurred with increased modeling time. To sum up, our current research indicates that the cognitive function under SM exposure is consistently maintained or potentially even being enhanced over both short and long durations. The underlying mechanisms are intricate and potentially linked to the differential expression of hippocampal-associated genes and alterations in synaptic function, with these effects being time-dependent. The present study will lay the experimental and theoretical foundation of the multi-level mechanism of cognitive function under space flight.

Enhanced neuronal activity by suffruticosol A extracted from Paeonia lactiflora via partly BDNF signaling in scopolamine-induced memory-impaired mice

Neurodegenerative diseases are explained by progressive defects of cognitive function and memory. These defects of cognition and memory dysfunction can be induced by the loss of brain-derived neurotrophic factors (BDNF) signaling. Paeonia lactiflora is a traditionally used medicinal herb in Asian countries and some beneficial effects have been reported, including anti-oxidative, anti-inflammatory, anti-cancer activity, and potential neuroprotective effects recently. In this study, we found that suffruticosol A is a major compound in seeds of Paeonia lactiflora. When treated in a SH-SY5 cell line for measuring cell viability and cell survival, suffruticosol A increased cell viability (at 20 µM) and recovered scopolamine-induced neurodegenerative characteristics in the cells. To further confirm its neural amelioration effects in the animals, suffruticosol A (4 or 15 ng, twice a week) was administered into the third ventricle beside the brain of C57BL/6 mice for one month then the scopolamine was intraperitoneally injected into these mice to induce impairments of cognition and memory before conducting behavioral experiments. Central administration of suffruticosol A into the brain restored the memory and cognition behaviors in mice that received the scopolamine. Consistently, the central treatments of suffruticosol A showed rescued cholinergic deficits and BDNF signaling in the hippocampus of mice. Finally, we measured the long-term potentiation (LTP) in the hippocampal CA3–CA1 synapse to figure out the restoration of the synaptic mechanism of learning and memory. Bath application of suffruticosol A (40 µM) improved LTP impairment induced by scopolamine in hippocampal slices. In conclusion, the central administration of suffruticosol A ameliorated neuronal effects partly through elevated BDNF signaling.

The central administration of vitisin a, extracted from Vitis vinifera, improves cognitive function and related signaling pathways in a scopolamine-induced dementia model

Neurodegenerative disorders, such as Alzheimer’s disease (AD), are characterized by cognitive function loss and progressive memory impairment. Vitis vinifera, which is consumed in the form of fruits and wines in various countries, contains several dietary stilbenoids that have beneficial effects on neuronal disorders related to cognitive impairment. However, few studies have investigated the hypothalamic effects of vitisin A, a resveratrol tetramer derived from V. vinifera stembark, on cognitive functions and related signaling pathways. In this study, we conducted in vitro, ex vivo, and in vivo experiments with multiple biochemical and molecular analyses to investigate its pharmaceutical effects on cognitive functions. Treatment with vitisin A increased cell viability and cell survival under H2O2-exposed conditions in a neuronal SH-SY5 cell line. Ex vivo experiments showed that vitisin A treatment restored the scopolamine-induced disruption of long-term potentiation (LTP) in the hippocampal CA3-CA1 synapse, indicating the restoration of synaptic mechanisms of learning and memory. Consistently, central administration of vitisin A ameliorated scopolamine-induced disruptions of cognitive and memory functions in C57BL/6 mice, as evidenced by Y-maze and passive avoidance tests. Further studies showed that vitisin A upregulates BDNF-CREB signaling in the hippocampus. Together, our findings suggest that vitisin A exhibits neuroprotective effects, at least partially, by upregulating BDNF-CREB signaling and LTP.

GluN2B-NMDAR subunit contribution on synaptic plasticity: A phenomenological model for CA3-CA1 synapses.

Synaptic plasticity is believed to be a key mechanism underlying learning and memory. We developed a phenomenological N-methyl-D-aspartate (NMDA) receptor-based voltage-dependent synaptic plasticity model for synaptic modifications at hippocampal CA3-CA1 synapses on a hippocampal CA1 pyramidal neuron. The model incorporates the GluN2A-NMDA and GluN2B-NMDA receptor subunit-based functions and accounts for the synaptic strength dependence on the postsynaptic NMDA receptor composition and functioning without explicitly modeling the NMDA receptor-mediated intracellular calcium, a local trigger of synaptic plasticity. We embedded the model into a two-compartmental model of a hippocampal CA1 pyramidal cell and validated it against experimental data of spike-timing-dependent synaptic plasticity (STDP), high and low-frequency stimulation. The developed model predicts altered learning rules in synapses formed on the apical dendrites of the detailed compartmental model of CA1 pyramidal neuron in the presence of the GluN2B-NMDA receptor hypofunction and can be used in hippocampal networks to model learning in health and disease.

Hippocampal CB1 receptor mediates antidepressant-like effect of synthetic cannabinoid-HU210 in acute despair reaction model in mice

Growing evidence suggests that stress may contribute to the pathophysiology of depression. The alleviation of depressive symptoms is one of the most attractive medical applications of cannabis. Here, we investigated the antidepressant-like actions of synthetic cannabinoid-HU210 in acute despair response and explored the possible underlying mechanisms. Acute stress, induced by forced-swimming, induced depression-like behavior in the sucrose preference test (SPT). HU-210 (50 μg/kg) displayed anti-depressant like effect in the forced swim test in naïve mice and decreased depression-like behavior in the SPT, induced by forced swim stress. Pretreatment with AM251, an inhibitor of CB1R or inhibition of long-term depression (LTD) at hippocampal CA3-CA1 synapses by Tat-GluR2 attenuated the antidepressant like action of HU-210. These results indicate that HU210 produces antidepressant-like effects in acute stress and its underlying mechanism may be related to CB1R activation and hence hippocampal LTD production invivo. Synthetic cannabis or cannabis-related drugs may be used as an early intervention after acute stress exposure to prevent or at least reduce depression-like behaviors.

Recognition Memory Induces Natural LTP-like Hippocampal Synaptic Excitation and Inhibition.

Synaptic plasticity is a cellular process involved in learning and memory by which specific patterns of neural activity adapt the synaptic strength and efficacy of the synaptic transmission. Its induction is governed by fine tuning between excitatory/inhibitory synaptic transmission. In experimental conditions, synaptic plasticity can be artificially evoked at hippocampal CA1 pyramidal neurons by repeated stimulation of Schaffer collaterals. However, long-lasting synaptic modifications studies during memory formation in physiological conditions in freely moving animals are very scarce. Here, to study synaptic plasticity phenomena during recognition memory in the dorsal hippocampus, field postsynaptic potentials (fPSPs) evoked at the CA3–CA1 synapse were recorded in freely moving mice during object-recognition task performance. Paired pulse stimuli were applied to Schaffer collaterals at the moment that the animal explored a new or a familiar object along different phases of the test. Stimulation evoked a complex synaptic response composed of an ionotropic excitatory glutamatergic fEPSP, followed by two inhibitory responses, an ionotropic, GABAA-mediated fIPSP and a metabotropic, G-protein-gated inwardly rectifying potassium (GirK) channel-mediated fIPSP. Our data showed the induction of LTP-like enhancements for both the glutamatergic and GirK-dependent components of the dorsal hippocampal CA3–CA1 synapse during the exploration of novel but not familiar objects. These results support the contention that synaptic plasticity processes that underlie hippocampal-dependent memory are sustained by fine tuning mechanisms that control excitatory and inhibitory neurotransmission balance.

ATP-binding cassette protein ABCA7 deficiency impairs sphingomyelin synthesis, cognitive discrimination, and synaptic plasticity in the entorhinal cortex

Sphingomyelin (SM) is an abundant plasma membrane and plasma lipoprotein sphingolipid. We previously reported that ATP-binding cassette family A protein 1 (ABCA1) deficiency in humans and mice decreases plasma SM levels. However, overexpression, induction, downregulation, inhibition, and knockdown of ABCA1 in human hepatoma Huh7 cells did not decrease SM efflux. Using unbiased siRNA screening, here, we identified that ABCA7 plays a role in the biosynthesis and efflux of SM without affecting cellular uptake and metabolism. Since loss of function mutations in the ABCA7 gene exhibit strong associations with late-onset Alzheimer’s disease across racial groups, we also studied the effects of ABCA7 deficiency in the mouse brain. Brains of ABCA7-deficient (KO) mice, compared with WT, had significantly lower levels of several SM species with long chain fatty acids. In addition, we observed that older KO mice exhibited behavioral deficits in cognitive discrimination in the active place avoidance task. Next, we performed synaptic transmission studies in brain slices obtained from older mice. We found anomalies in synaptic plasticity at the intracortical synapse in layer II/III of the lateral entorhinal cortex but not in the hippocampal CA3-CA1 synapses in KO mice. These synaptic abnormalities in KO brain slices were rescued with extracellular SM supplementation but not by supplementation with phosphatidylcholine. Taken together, these studies identify a role of ABCA7 in brain SM metabolism and the importance of SM in synaptic plasticity and cognition, as well as provide a possible explanation for the association between ABCA7 and late-onset Alzheimer’s disease.

Differential vulnerability of hippocampal CA3-CA1 synapses to A\u03b2

Amyloid-beta (Aβ) and tau protein are both involved in the pathogenesis of Alzheimer’s disease. Aβ produces synaptic deficits in wild-type mice that are not seen in Mapt−/− mice, suggesting that tau protein is required for these effects of Aβ. However, whether some synapses are more selectively affected and what factors may determine synaptic vulnerability to Aβ are poorly understood. Here we first observed that burst timing-dependent long-term potentiation (b-LTP) in hippocampal CA3-CA1 synapses, which requires GluN2B subunit-containing NMDA receptors (NMDARs), was inhibited by human Aβ1–42 (hAβ) in wild-type (WT) mice, but not in tau-knockout (Mapt−/−) mice. We then tested whether NMDAR currents were affected by hAβ; we found that hAβ reduced the postsynaptic NMDAR current in WT mice but not in Mapt−/− mice, while the NMDAR current was reduced to a similar extent by the GluN2B-selective NMDAR antagonist Ro 25–6981. To further investigate a possible difference in GluN2B-containing NMDARs in Mapt−/− mice, we used optogenetics to compare NMDAR/AMPAR ratio of EPSCs in CA1 synapses with input from left vs right CA3. It was previously reported in WT mice that hippocampal synapses in CA1 that receive input from the left CA3 display a higher NMDAR charge transfer and a higher Ro-sensitivity than synapses in CA1 that receive input from the right CA3. Here we observed the same pattern in Mapt−/− mice, thus differential NMDAR subunit expression does not explain the difference in hAβ effect on LTP. Finally, we asked whether synapses with left vs right CA3 input are differentially affected by hAβ in WT mice. We found that NMDAR current in synapses with input from the left CA3 were reduced while synapses with input from the right CA3 were unaffected by acute hAβ exposure. These results suggest that hippocampal CA3-CA1 synapses with presynaptic axon originating in the left CA3 are selectively vulnerable to Aβ and that a genetic knock out of tau protein protects them from Aβ synaptotoxicity.

Identification and characterization of long non-coding RNA Carip in modulating spatial learning and memory.

CaMKII has long been known to be a key effector for synaptic plasticity. Recent studies have shown that a variety of modulators interact with the subunits of CaMKII to regulate the long-term potentiation (LTP) of hippocampal neurons. However, whether long non-coding RNAs modulate the activity of CaMKII and affect synaptic plasticity is still elusive. Here, we identify a previously uncharacterized long non-coding RNA Carip that functions as a scaffold, specifically interacts with CaMKIIβ, and regulates the phosphorylation of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-d-aspartate (NMDA) receptor subunits in the hippocampus. The absence of Carip causes dysfunction of synaptic transmission and attenuates LTP in hippocampal CA3-CA1 synapses, which further leads to impairment of spatial learning and memory. In summary, our findings demonstrate that Carip modulates long-term synaptic plasticity by changing AMPA receptor and NMDA receptor activities, thereby affecting spatial learning and memory in mice.

G-Protein-Gated Inwardly Rectifying Potassium (Kir3/GIRK) Channels Govern Synaptic Plasticity That Supports Hippocampal-Dependent Cognitive Functions in Male Mice.

The G-protein-gated inwardly rectifying potassium (Kir3/GIRK) channel is the effector of many G-protein-coupled receptors (GPCRs). Its dysfunction has been linked to the pathophysiology of Down syndrome, Alzheimer's and Parkinson's diseases, psychiatric disorders, epilepsy, drug addiction, or alcoholism. In the hippocampus, GIRK channels decrease excitability of the cells and contribute to resting membrane potential and inhibitory neurotransmission. Here, to elucidate the role of GIRK channels activity in the maintenance of hippocampal-dependent cognitive functions, their involvement in controlling neuronal excitability at different levels of complexity was examined in C57BL/6 male mice. For that purpose, GIRK activity in the dorsal hippocampus CA3-CA1 synapse was pharmacologically modulated by two drugs: ML297, a GIRK channel opener, and Tertiapin-Q (TQ), a GIRK channel blocker. Ex vivo, using dorsal hippocampal slices, we studied the effect of pharmacological GIRK modulation on synaptic plasticity processes induced in CA1 by Schaffer collateral stimulation. In vivo, we performed acute intracerebroventricular (i.c.v.) injections of the two GIRK modulators to study their contribution to electrophysiological properties and synaptic plasticity of dorsal hippocampal CA3-CA1 synapse, and to learning and memory capabilities during hippocampal-dependent tasks. We found that pharmacological disruption of GIRK channel activity by i.c.v. injections, causing either function gain or function loss, induced learning and memory deficits by a mechanism involving neural excitability impairments and alterations in the induction and maintenance of long-term synaptic plasticity processes. These results support the contention that an accurate control of GIRK activity must take place in the hippocampus to sustain cognitive functions.SIGNIFICANCE STATEMENT Cognitive processes of learning and memory that rely on hippocampal synaptic plasticity processes are critically ruled by a finely tuned neural excitability. G-protein-gated inwardly rectifying K+ (GIRK) channels play a key role in maintaining resting membrane potential, cell excitability and inhibitory neurotransmission. Here, we demonstrate that modulation of GIRK channels activity, causing either function gain or function loss, transforms high-frequency stimulation (HFS)-induced long-term potentiation (LTP) into long-term depression (LTD), inducing deficits in hippocampal-dependent learning and memory. Together, our data show a crucial GIRK-activity-mediated mechanism that governs synaptic plasticity direction and modulates subsequent hippocampal-dependent cognitive functions.

Central Administration of Ampelopsin A Isolated from Vitis vinifera Ameliorates Cognitive and Memory Function in a Scopolamine-Induced Dementia Model.

Neurodegenerative diseases are characterized by the progressive degeneration of the function of the central nervous system or peripheral nervous system and the decline of cognition and memory abilities. The dysfunctions of the cognitive and memory battery are closely related to inhibitions of neurotrophic factor (BDNF) and brain-derived cAMP response element-binding protein (CREB) to associate with the cholinergic system and long-term potentiation. Vitis vinifera, the common grapevine, is viewed as the important dietary source of stilbenoids, particularly the widely-studied monomeric resveratrol to be used as a natural compound with wide-ranging therapeutic benefits on neurodegenerative diseases. Here we found that ampelopsin A is a major compound in V. vinifera and it has neuroprotective effects on experimental animals. Bath application of ampelopsin A (10 ng/µL) restores the long-term potentiation (LTP) impairment induced by scopolamine (100 μM) in hippocampal CA3-CA1 synapses. Based on these results, we administered the ampelopsin A (10 ng/µL, three times a week) into the third ventricle of the brain in C57BL/6 mice for a month. Chronic administration of ampelopsin A into the brain ameliorated cognitive memory-behaviors in mice given scopolamine (0.8 mg/kg, i.p.). Studies of mice’s hippocampi showed that the response of ampelopsin A was responsible for the restoration of the cholinergic deficits and molecular signal cascades via BDNF/CREB pathways. In conclusion, the central administration of ampelopsin A contributes to increasing neurocognitive and neuroprotective effects on intrinsic neuronal excitability and behaviors, partly through elevated BDNF/CREB-related signaling.

Increased Excitability and Heightened Magnitude of Long-Term Potentiation at Hippocampal CA3-CA1 Synapses in a Mouse Model of Neonatal Hyperoxia Exposure.

Preterm infants exposed to supraphysiological oxygen (hyperoxia) during the neonatal period have hippocampal atrophy and cognitive dysfunction later in childhood and as adolescents. Previously, we reported that 14-week-old adult mice exposed to hyperoxia as newborns had spatial memory deficits and hippocampal shrinkage, findings that mirror those of human adolescents who were born preterm. The area CA1 region of the hippocampus that is crucial for spatial learning and memory is highly vulnerable to oxidative stress. In this study, we investigated the long-term impact of neonatal hyperoxia exposure on hippocampal CA3–CA1 synaptic function. Male and female C57BL/6J mouse pups were continuously exposed to either 85% normobaric oxygen or air between postnatal days 2–14. Hippocampal slice electrophysiology at CA3–CA1 synapses was then performed at 14 weeks of age. We observed that hyperoxia exposed mice have heightened strength of basal synaptic transmission measured in input-output curves, increased fiber volley amplitude indicating increased axonal excitability, and heightened LTP magnitude at CA3–CA1 synapses, likely a consequence of increased postsynaptic depolarization during tetanus. These data demonstrate that supraphysiological oxygen exposure during the critical neonatal developmental period leads to pathologically heightened CA3–CA1 synaptic function during early adulthood which may contribute to hippocampal shrinkage and learning and memory deficits we previously reported. Furthermore, these results will help shed light on the consequences of hyperoxia exposure on the development of hippocampal synaptic circuit abnormalities that could be contributing to cognitive deficits in children born preterm.

Astrocyte-mediated switch in spike timing-dependent plasticity during hippocampal development

Presynaptic spike timing-dependent long-term depression (t-LTD) at hippocampal CA3-CA1 synapses is evident until the 3rd postnatal week in mice, disappearing during the 4th week. At more mature stages, we found that the protocol that induced t-LTD induced t-LTP. We characterized this form of t-LTP and the mechanisms involved in its induction, as well as that driving this switch from t-LTD to t-LTP. We found that this t-LTP is expressed presynaptically at CA3-CA1 synapses, as witnessed by coefficient of variation, number of failures, paired-pulse ratio and miniature responses analysis. Additionally, this form of presynaptic t-LTP does not require NMDARs but the activation of mGluRs and the entry of Ca2+ into the postsynaptic neuron through L-type voltage-dependent Ca2+ channels and the release of Ca2+ from intracellular stores. Nitric oxide is also required as a messenger from the postsynaptic neuron. Crucially, the release of adenosine and glutamate by astrocytes is required for t-LTP induction and for the switch from t-LTD to t-LTP. Thus, we have discovered a developmental switch of synaptic transmission from t-LTD to t-LTP at hippocampal CA3-CA1 synapses in which astrocytes play a central role and revealed a form of presynaptic LTP and the rules for its induction.

Increased O-GlcNAcylation rapidly decreases GABAAR currents in hippocampus but depresses neuronal output

O-GlcNAcylation, a post-translational modification involving O-linkage of β-N-acetylglucosamine to Ser/Thr residues on target proteins, is increasingly recognized as a critical regulator of synaptic function. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. An acute increase in O-GlcNAcylation can affect neuronal communication by inducing long-term depression (LTD) of excitatory transmission at hippocampal CA3-CA1 synapses, as well as suppressing hyperexcitable circuits in vitro and in vivo. Despite these findings, to date, no studies have directly examined how O-GlcNAcylation modulates the efficacy of inhibitory neurotransmission. Here we show an acute increase in O-GlcNAc dampens GABAergic currents onto principal cells in rodent hippocampus likely through a postsynaptic mechanism, and has a variable effect on the excitation/inhibition balance. The overall effect of increased O-GlcNAc is reduced synaptically-driven spike probability via synaptic depression and decreased intrinsic excitability. Our results position O-GlcNAcylation as a novel regulator of the overall excitation/inhibition balance and neuronal output.

On the Modulatory Roles of Neuregulins/ErbB Signaling on Synaptic Plasticity.

Neuregulins (NRGs) are a family of epidermal growth factor-related proteins, acting on tyrosine kinase receptors of the ErbB family. NRGs play an essential role in the development of the nervous system, since they orchestrate vital functions such as cell differentiation, axonal growth, myelination, and synapse formation. They are also crucially involved in the functioning of adult brain, by directly modulating neuronal excitability, neurotransmission, and synaptic plasticity. Here, we provide a review of the literature documenting the roles of NRGs/ErbB signaling in the modulation of synaptic plasticity, focusing on evidence reported in the hippocampus and midbrain dopamine (DA) nuclei. The emerging picture shows multifaceted roles of NRGs/ErbB receptors, which critically modulate different forms of synaptic plasticity (LTP, LTD, and depotentiation) affecting glutamatergic, GABAergic, and DAergic synapses, by various mechanisms. Further, we discuss the relevance of NRGs/ErbB-dependent synaptic plasticity in the control of brain processes, like learning and memory and the known involvement of NRGs/ErbB signaling in the modulation of synaptic plasticity in brain’s pathological conditions. Current evidence points to a central role of NRGs/ErbB receptors in controlling glutamatergic LTP/LTD and GABAergic LTD at hippocampal CA3–CA1 synapses, as well as glutamatergic LTD in midbrain DA neurons, thus supporting that NRGs/ErbB signaling is essential for proper brain functions, cognitive processes, and complex behaviors. This suggests that dysregulated NRGs/ErbB-dependent synaptic plasticity might contribute to mechanisms underlying different neurological and psychiatric disorders.

Lack of Neuronal Glycogen Impairs Memory Formation and Learning-Dependent Synaptic Plasticity in Mice.

Since brain glycogen is stored mainly in astrocytes, the role of this polysaccharide in neurons has been largely overlooked. To study the existence and relevance of an active neuronal glycogen metabolism in vivo, we generated a mouse model lacking glycogen synthase specifically in the Camk2a-expressing postnatal forebrain pyramidal neurons (GYS1Camk2a–KO), which include the prefrontal cortex and the CA3 and CA1 cell layers of the hippocampus. The latter are involved in memory and learning processes and participate in the hippocampal CA3-CA1 synapse, the function of which can be analyzed electrophysiologically. Long-term potentiation evoked in the hippocampal CA3-CA1 synapse was decreased in alert behaving GYS1Camk2a–KO mice. They also showed a significant deficiency in the acquisition of an instrumental learning task – a type of associative learning involving prefrontal and hippocampal circuits. Interestingly, GYS1Camk2a–KO animals did not show the greater susceptibility to hippocampal seizures and myoclonus observed in animals completely depleted of glycogen in the whole CNS. These results unequivocally demonstrate the presence of an active glycogen metabolism in neurons in vivo and reveal a key role of neuronal glycogen in the proper acquisition of new motor and cognitive abilities, and in the changes in synaptic strength underlying such acquisition.