Hippocampal Glutamate Research Articles

Ropivacaine Protects against Memory Impairment and Hippocampal Damage in a Rat Neurodegeneration Model

Background: Ropivacaine, a long-acting amide local anesthetic agent, has been demonstrated to inhibit glutamatergic transmission. Glutamate neurotoxicity plays a pivotal role in the pathogenesis of brain disorders. The purpose of this study is to investigate the neuroprotective effect of ropivacaine against brain damage induced by kainic acid (KA), an analogue of glutamate. Methods: Rats were injected with ropivacaine (0.4 or 2 mg/kg, intraperitoneal) 30 min before KA treatment (15 mg/kg, intraperitoneal). KA-induced memory impairment was evaluated using the Morris water maze test. Extracellular hippocampal glutamate levels were assessed using high-performance liquid chromatography. Neuronal death was verified using Fluoro-Jade B and neutral red staining, and apoptosis was determined through terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL). Western blotting was conducted to assay the levels of activated (cleaved) caspase-3 and the phosphorylation of different mitogen-activated protein kinases (MAPKs). ­Results: Ropivacaine pretreatment effectively prevented KA-induced memory impairment. KA-induced elevations of ­glutamate release in rat hippocampi were inhibited by pretreatment with ropivacaine. Histopathological and TUNEL staining analyzes showed that ropivacaine inhibited KA-induced neuronal death and apoptosis in the hippocampal CA3 region. KA-induced caspase-3 activation and MAPKs phosphorylation in the hippocampus were also reduced by ropivacaine pretreatment. Conclusions: This study ­demonstrates that ropivacaine executes a protective action against KA-induced neuronal damage and apoptosis in vivo. Protective effects may be caused by glutamate level reduction, caspase-3 activation suppression, and MAPKs phosphorylation reduction. Our findings indicate that ropivacaine can benefit prevention or treatment of glutamate excitotoxicity-related neurodegenerative diseases.

Effect of 17β estradiol on propofol-induced long-term cognitive dysfunction in developing rats: the relationship with hippocampal Glu/GABA

Objective To evaluate the effect of 17β estradiol on propofol-induced long-term cognitive dysfunction in developing rats and the relationship with hippocampal glutamate (Glu)/γ-aminobutyric acid (GABA). Methods Sixty healthy male Sprague-Dawley rats, aged 7 days, weighing 11-18 g, were divided into 5 groups (n=12 each) using a random number table method: dimethyl sulfoxide (DMSO) group, fat emulsion group (group F), 17β estradiol group (group E), propofol group (group P) and propofol plus 17β estradiol group (group P+ E).17β estradiol 600 μg/kg was subcutaneously injected in group E, and the equal volume of DMSO was given instead in group DMSO.Propofol 75 mg/kg was intraperitoneally injected in group P, and the equal volume of fat emulsion was given instead in group F. 17β estradiol 600 μg/kg was subcutaneously injected and 30 min later propofol 75 mg/kg was intraperitoneally injected in group P+ E.Injection was performed once every 24 h for 7 consecutive days in each group.Morris water maze test was performed at 60 days of age.The rats were sacrificed after the end of Morris water maze test and hippocampi were removed for determination of Glu content (by ultraviolet colorimetry method) and GABA content (using enzyme-linked immunosorbent assay) in hippocampal tissues.Glu/GABA ratio was calculated. Results There was no significant difference in the escape latency, the number of crossing the original platform, percentage of time spent in target quadrant, Glu content or Glu/GABA ratio between group DMSO, group F and group E (P>0.05). There was no significant difference in GABA content among the five groups (P>0.05). Compared with group F, the escape latency was significantly prolonged, the number of crossing the original platform was reduced, and the percentage of time spent in target quadrant, Glu content and Glu/GABA ratio were decreased in group P (P<0.05). Compared with group P, the escape latency was significantly shortened, the number of crossing the original platform was increased, and the percentage of time spent in target quadrant, Glu content and Glu/GABA ratio were increased in group P+ E (P<0.05). Conclusion 17β estradiol can improve propofol-induced long-term cognitive dysfunction and the mechanism may be related to maintaining hippocampal Glu/GABA balance in developing rats. Key words: Propofol; Estradiol; Cognition disorders; Glutamic acid; gamma-Aminobutyric acid; Hippocampus

Analysis of neurotransmitter levels in addiction-related brain regions during synthetic cathinone self-administration in male Sprague-Dawley rats.

Synthetic cathinones are used as stimulants of abuse. Different stimulants may induce distinct rates of disease progression, yielding neurochemical changes that may vary across brain regions or neurotransmitter systems. This research sought to behaviorally and chemically differentiate stages of synthetic cathinone abuse through rodent self-administration and measurement of the neurotransmitter profile in multiple brain regions. Male rats were trained to self-administer α-PVP, mephedrone (4MMC), or saline. Half of each drug group stopped self-administering after autoshaping; the other half self-administered for another 21days. Brain tissue from amygdala, hippocampus, hypothalamus, PFC, striatum, and thalamus was profiled with electrochemical detection to assess neurotransmitter levels. During autoshaping, the majority of infusions were delivered noncontingently. In the self-administration phase, rats responded more for α-PVP and 4MMC than for saline, demonstrating that both synthetic cathinones were reinforcing. Longer durations of exposure elevated 5-HIAA in hypothalamus, PFC, and hippocampus, indicating that learning may produce changes in addiction-related brain regions. Both synthetic cathinones decreased norepinephrine in hippocampus, while α-PVP decreased glutamate in hippocampus and PFC, and 4MMC decreased glutamate in thalamus. Furthermore, α-PVP increased dopaminergic metabolites in striatum, whereas 4MMC decreased serotonin in the amygdala, hippocampus, and PFC. Interestingly, neither synthetic cathinone affected dopamine levels despite their functional effects on the dopaminergic system. In summary, the neurotransmitter changes observed here suggest that synthetic cathinone use likely produces sequential neurochemical changes during the transition from use to abuse. Consequently, treatment need may differ depending on the progression of synthetic cathinone abuse.

Neurofilament light interaction with GluN1 modulates neurotransmission and schizophrenia-associated behaviors

Neurofilament (NFL) proteins have recently been found to play unique roles in synapses. NFL is known to interact with the GluN1 subunit of N-methyl-d-aspartic acid (NMDAR) and be reduced in schizophrenia though functional consequences are unknown. Here we investigated whether the interaction of NFL with GluN1 modulates synaptic transmission and schizophrenia-associated behaviors. The interaction of NFL with GluN1 was assessed by means of molecular, pharmacological, electrophysiological, magnetic resonance spectroscopy (MRS), and schizophrenia-associated behavior analyses. NFL deficits cause an NMDAR hypofunction phenotype including abnormal hippocampal function, as seen in schizophrenia. NFL−/− deletion in mice reduces dendritic spines and GluN1 protein levels, elevates ubiquitin-dependent turnover of GluN1 and hippocampal glutamate measured by MRS, and depresses hippocampal long-term potentiation. NMDAR-related behaviors are also impaired, including pup retrieval, spatial and social memory, prepulse inhibition, night-time activity, and response to NMDAR antagonist, whereas motor deficits are minimal. Importantly, partially lowering NFL in NFL+/− mice to levels seen regionally in schizophrenia, induced similar but milder NMDAR-related synaptic and behavioral deficits. Our findings support an emerging view that central nervous system neurofilament subunits including NFL in the present report, serve distinctive, critical roles in synapses relevant to neuropsychiatric diseases.

Hippocampal glutamate metabolites and glial activation in clinical high risk and first episode psychosis.

Alterations in glutamate neurotransmission have been implicated in the pathophysiology of schizophrenia, as well as in symptom severity and cognitive deficits. The hippocampus, in particular, is a site of key functional and structural abnormalities in schizophrenia. Yet few studies have investigated hippocampal glutamate in antipsychotic-naïve first episode psychosis patients or in individuals at clinical high risk (CHR) of developing psychosis. Using proton magnetic resonance spectroscopy (1H-MRS), we investigated glutamate metabolite levels in the left hippocampus of 25 CHR (19 antipsychotic-naïve), 16 patients with first-episode psychosis (13 antipsychotic-naïve) and 31 healthy volunteers. We also explored associations between hippocampal glutamate metabolites and glial activation, as indexed by [18F]FEPPA positron emission tomography (PET); symptom severity; and cognitive function. Groups differed significantly in glutamate plus glutamine (Glx) levels (F(2, 69) = 6.39, p = 0.003). Post-hoc analysis revealed that CHR had significantly lower Glx levels than both healthy volunteers (p = 0.003) and first-episode psychosis patients (p = 0.050). No associations were found between glutamate metabolites and glial activation. Our findings suggest that glutamate metabolites are altered in CHR.

High-fat diet suppresses the astrocytic process arborization and downregulates the glial glutamate transporters in the hippocampus of mice

Metabolic disorders induce adverse effects on brain functions. The hippocampus is one of the most vulnerable regions to metabolic disorders. Disrupted neuroplasticity is a major cause of hippocampus-related behavioral impairments, including memory loss, anxiety, and depression. Astrocytes support processes of neuroplasticity. However, whether metabolic disorders induce changes in astrocytes and their roles in affective disorders is relatively unclear. To answer this question, we fed 8-week-old male C57BL/6 mice with a high-fat diet (HFD) for 12 weeks to induce metabolic disruption and then examined their performance of hippocampus-related memory, and anxiety- and depression-like behaviors. The morphology of astrocytes and the expression of astrocytic neuroplasticity-related proteins in the hippocampus were also assessed. The results showed that HFD led to obesity, systemic insulin resistance and dysregulated lipid metabolism in mice. HFD induced depression-like behaviors, but not anxiety or memory impairment. Furthermore, HFD increased the expression of GFAP, shortened the processes of GFAP+ cells, and downregulated the expression of astrocytic neuroplasticity-related protein, GLAST, GLT-1, and connexin-43 in the hippocampi. In conclusion, HFD disturbs the function of hippocampal astrocytes and induces depression-like behaviors in mice. A decrease of hippocampal glutamate transporters may play a critical role in the pathogenesis of metabolic disorder-related depression.

Long-Term Neurobehavioral Consequences of a Single Ketamine Neonatal Exposure in Rats: Effects on Cellular Viability and Glutamate Transport in Frontal Cortex and Hippocampus.

The neonatal exposure to general anesthetics has been associated with neuronal apoptosis and dendritic spines morphologic changes in the developing brain. Ketamine, a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is widely used in pediatric patients to induce general anesthesia, analgesia, and perioperative sedation. In the present study, we investigated short- and long-term effects of a single ketamine (20mg/kg, s.c.) neonatal exposure at postnatal day 7 in rats on the hippocampal and frontal cortical cellular viability. Additionally, putative neurochemical alterations and neurobehavioral impairments were evaluated in the adulthood. Ketamine neonatal administration selectively decreased cellular viability in the hippocampus, but not in the frontal cortex, 24h after the treatment. Interestingly, a single ketamine neonatal exposure prevented the vulnerability to glutamate-induced neurotoxicity in the frontal cortex of adult rats. No short- or long-term damage to cellular membranes, as an indicative of cell death, was observed in hippocampal or cortical slices. However, ketamine induced a long-term increase in hippocampal glutamate uptake. Regarding behavioral analysis, neonatal ketamine exposure did not alter locomotor activity and anxiety-related parameters evaluated in the open-field test. However, ketamine administration disrupted the hippocampal-dependent object recognition ability of adult rats, while improved the motor coordination addressed on the rotarod. These findings indicate that a single neonatal ketamine exposure induces a short-term reduction in the hippocampal, but not in cortical, cellular viability, and long-term alterations in hippocampal glutamate transport, improvement on motor performance, and short-term recognition memory impairment.

Inter-individual differences in serotonin and glutamate co-transmission reflect differentiation in context-induced conditioned 50-kHz USVs response after morphine withdrawal

A growing body of research provides compelling evidence that in rats 50-kHz USVs are a form of expression of positive emotions. Context-induced 50-kHz USVs emission is variable among rats, indicating individual differences in contextual response bound up with pharmacological reward. The aims of this study were to: extract the most important neurotransmitters related to context-induced conditioned 50-kHz USVs response; find biological basis of existing inter-individual differences in context-induced conditioned 50-kHz USVs response; create a model of all-to-all neurotransmitters correlations. The data collected here confirms that re-exposure to the context of morphine administration after the withdrawal period increases the level of 50-kHz USVs and this contextual response is associated with elevated serotonin concentrations in amygdala, hippocampus and mPFC and with increased Glu/Gln ratio in nucleus accumbens. The concentration of serotonin increases simultaneously in amygdala, nucleus accumbens and hippocampus. Moreover, 5-HT concentration in amygdala is bound up with glutamate level in this structure as well as in hippocampus. Furthermore, Glu/Gln ratio in nucleus accumbens has strong associations with Glu/Gln ratio simultaneously in VTA, amygdala, striatum and hippocampus. All-to-all-analysis indicate that concentration of glutamate in hippocampus is proportional to glutamate in VTA and GABA concentration in the hippocampus. We have also demonstrated that Glu/GABA ratio in VTA and amygdala was elevated after post withdrawal re-exposure to the pharmacological reward paired context. Presented analysis indicates a strong correlation between serotonergic and glutamatergic systems in context-induced conditioned response. The strength of this co-transmission correlates with the number of 50-kHz USVs emitted in response to morphine-paired context.

P.1.015 - Influence of prebiotic intake on olanzapine-mediated weight gain, central receptors, peripheral biomarkers, and gut microbiota

Olanzapine is the first-line antipsychotic treatment for schizophrenia, but often leads to secondary health concerns such as metabolic syndrome and weight gain. Studies in rats have shown that chronic olanzapine administration induces weight gain [1] and reduces hippocampal glutamate N-methyl-D-Aspartate receptor (NMDAR) levels, the latter which may hinder the recovery of cognitive function in schizophrenia patients. We have shown that dietary augmentation of beneficial gut bacteria using the commercially available prebiotic Bimuno ™ galacto-oligosaccharides (B-GOS ® ) increases central levels of NMDAR subunits in rodents [2,3]. The aim of this study was to determine whether the effects of olanzapine on weight gain and peripheral effects are influenced by B-GOS® intake in rats. Adult female Sprague-Dawley rats were provided with a B-GOS ® (0.5g/kg/day) solution or water for 21 days, and received a single, daily, intraperitoneal injection of olanzapine or saline on days 8-21. Weight gain and water intake were monitored daily. We determined whether B-GOS ® influenced olanzapine-associated weight gain, and central NMDAR and serotonin receptor expression. Circulating levels of acetate, IL-1β, IL-8 and TNFα as well as liver acetyl-CoA Carboxylase (ACC), white adipose tissue acetate receptor GPR43, and specific faecal bacteria genera were also measured to provide mechanistic information. Two-way ANOVAs were used to analyse all data, with repeated measures included to explore weight gain. Olanzapine induced significant weight gain (p ® -fed rats. Significant effect of treatment was observed on hippocampal GluN1 mRNA abundance (p = 0.034), where olanzapine significantly increased (+17%) levels in the absence of B-GOS ® (p = 0.040). Plasma acetate concentrations increased following B-GOS ® or olanzapine administration alone, but reduced when prebiotic and drug were administered in combination. This pattern was paralleled by hepatic ACC mRNA expression. The abundance of WAT GPR43 mRNA was reduced by olanzapine, only in the absence of B-GOS ® . Co-administration of B-GOS ® and olanzapine also elevated plasma TNFα, which is reported to influence lipid metabolism. Finally, B-GOS ® elevated faecal Bifidobacterium Spp. and reduced some bacteria in the Firmicutes phylum, whilst olanzapine treatment either alone or with B-GOS ® , was without effect. The current study demonstrates a potential strategy to reduce olanzapine-mediated weight gain in schizophrenia without compromising a key central pharmacological action of this antipsychotic. We also demonstrate a NMDAR augmenting effect, supporting a potential pro-cognitive effect of the prebiotic. Our data also implies that elevated TNFα in B-GOS ® /olanzapine rats may contribute to the reduction in olanzapine-induced weight gain as pro-inflammatory TNFα is a recognised appetite suppressant. These data suggest that inclusion of B-GOS ® as an adjunct to olanzapine treatment in schizophrenia may prevent weight gain and have benefits on cognitive function in psychosis.

Astaxanthin protects against kainic acid-induced seizures and pathological consequences

Excitotoxic damage caused by increased glutamate levels is involved in the pathogenesis of neurodegenerative diseases. Astaxanthin, a natural carotenoid with multiple health benefits, inhibits glutamate release from the brain tissue; however, whether it possesses the ability to affect glutamate-induced brain injury is unknown. The present study investigated the neuroprotective effects of astaxanthin on kainic acid (KA)-induced excitotoxicity in rats and the possible underlying intracellular signaling pathway. The rats were orally administrated with astaxanthin (50 or 100 mg/kg) for 7 days (once a day), and KA (15 mg/kg) was administered intraperitoneally at 1 h after the final administration. The results revealed that KA induced seizures, increased the hippocampal glutamate levels, caused considerable neuronal death and microglial activation in the hippocampal CA3 regions, and increased the production of proinflammatory cytokines. Astaxanthin pretreatment prevented these changes. Furthermore, astaxanthin pretreatment increased the expression of neuronal cell survival-related factors, including phosphorylated Akt, phosphorylated glycogen synthase kinase-3β, and Bcl-2 in the hippocampus of KA-injected rats. These results suggested that astaxanthin can attenuate seizures, mitigate inflammation, augment survival signals, and prevent hippocampal neuronal damage in the animal model of KA-induced excitotoxicity.

Human Striatal Response to Reward Anticipation Linked to Hippocampal Glutamate Levels.

BackgroundDysfunctional reward processing is associated with a number of psychiatric disorders, such as addiction and schizophrenia. It is thought that reward is regulated mainly by dopamine transmission in the ventral striatum. Contemporary animal models suggest that striatal dopamine concentrations and associated behaviors are related to glutamatergic functioning in the ventral hippocampus. However, in humans the association between reward-related ventral striatal response and hippocampal glutamate levels is unclear.MethodsNineteen healthy participants were studied using proton magnetic resonance spectroscopy to measure hippocampal glutamate levels, and functional magnetic resonance imaging to assess striatal activation and functional connectivity during performance of a monetary incentive delay task.ResultsWe found that ventral striatal activation related to reward processing was correlated with hippocampal glutamate levels. In addition, context-dependent functional coupling was demonstrated between the ventral striatum and both the lingual gyrus and hippocampus during reward anticipation. Elevated hippocampal glutamate levels were inversely related to context-dependent functional connectivity between the ventral striatum and the anterior hippocampus while anticipating reward.ConclusionsThese findings indicate that human striatal responses to reward are influenced by hippocampal glutamate levels. This may be relevant for psychiatric disorders associated with abnormal reward processing such as addiction and schizophrenia.

Effect of decabrominated diphenyl ether exposure on spatial learning and memory, the expression and phosphorylation of hippocampal glutamate receptor subunits in adult Sprague-Dawley rats.

Previous studies have reported the potential developmental neurobehavioral effects of decabrominated diphenyl ethers (BDE 209) on developing animals, but the effects on adult animals are rare or controversial and the mechanism is not fully understood. In the present study, male adult Sprague-Dawley rats performed poor spatial learning and memory in Morris water maze after exposure to BDE 209 by gavage for 30 days. The expression of hippocampal glutamate receptor subunits NR1, NR2B and GluR1, the phosphorylation of NR2B subunit at Ser1301 (p-NR2B Ser1303) and GluR1 subunit at Ser831 (p-GluR1 Ser831) were all decreased, and the phosphorylation ratio of NR2B revealed an increasing trend after BDE 209 exposure. The present study provided evidence that BDE 209 could induce spatial learning and memory deficits in adult rats, and further explored the potential mechanism.

S100A9 Protein Aggregates Boost Hippocampal Glutamate Modifying Monoaminergic Neurochemistry: A Glutamate Antibody Sensitive Outcome on Alzheimer-like Memory Decline.

Alzheimer's disease (AD) involves dementia conceivably arising from integrated inflammatory processes, amyloidogenesis, and neuronal apoptosis. Glutamate can also cause neuronal death via excitotoxicity, and this is similarly implicated in some neurological diseases. The aim was to examine treatment with in vitro generated proinflammatory protein S100A9 aggregate species alone or with glutamate antibodies (Glu-Abs) on Morris water maze (MWM) spatial learning and memory performance in 12 month old mice. Amino acid and monoamine cerebral neurotransmitter metabolic changes were concurrently monitored. Initially, S100A9 fibrils were morphologically verified by atomic force microscopy and Thioflavin T assay. They were then administered intranasally alone or with Glu-Abs for 14 days followed by a 5 day MWM protocol before hippocampal and prefrontal cortical neurochemical analysis. S100A9 aggregates evoked spatial amnesia which correlated with disrupted glutamate and dopaminergic neurochemistry. Hippocampal glutamate release, elevation of DOPAC and HVA, as well as DOPAC/DA and HVA/DA ratios were subsequently reduced by Glu-Abs which simultaneously prevented the spatial memory deficit. The present outcomes emphasized the pathogenic nature of S100A9 fibrillar aggregates in causing spatial memory amnesia associated with enhanced hippocampal glutamate release and DA-ergic disruption in the aging brain. This finding might be exploited during dementia management through a neuroprotective strategy.

Opioid system contribution to the antidepressant-like action ofm-trifluoromethyl-diphenyl diselenide in mice: A compound devoid of tolerance and withdrawal syndrome

Animal and clinical researches indicate that the opioid system exerts a crucial role in the etiology of mood disorders and is a target for intervention in depression treatment. This study investigated the contribution of the opioid system to the antidepressant-like action of acute or repeated m-trifluoromethyl-diphenyl diselenide administration to Swiss mice. m-Trifluoromethyl-diphenyl diselenide (50 mg/kg, intragastric) produced an antidepressant-like action in the forced swimming test from 30 min to 24 h after treatment. This effect was blocked by the µ and δ-opioid receptor antagonists, naloxonazine (10 mg/kg, intraperitoneally) and naltrindole (3 mg/kg, intraperitoneally), and it was potentiated by a κ-opioid receptor antagonist, norbinaltrophimine (1 mg/kg, subcutaneously ). Combined treatment with subeffective doses of m-trifluoromethyl-diphenyl diselenide (10 mg/kg, intragastric) and morphine (1 mg/kg, subcutaneously) resulted in a synergistic antidepressant-like effect. The opioid system contribution to the m-trifluoromethyl-diphenyl diselenide antidepressant-like action was also demonstrated in the modified tail suspension test, decreasing mouse immobility and swinging time and increasing curling time, results similar to those observed using morphine, a positive control. Treatment with m-trifluoromethyl-diphenyl diselenide induced neither tolerance to the antidepressant-like action nor physical signs of withdrawal, which could be associated with the fact that m-trifluoromethyl-diphenyl diselenide did not change the mouse cortical and hippocampal glutamate uptake and release. m-Trifluoromethyl-diphenyl diselenide treatments altered neither locomotor nor toxicological parameters in mice. These findings demonstrate that m-trifluoromethyl-diphenyl diselenide elicited an antidepressant-like action by direct or indirect μ and δ-opioid receptor activation and the κ-opioid receptor blockade, without inducing tolerance, physical signs of withdrawal and toxicity.

In SilicoModel-driven Assessment of the Effects of Brain-derived Neurotrophic Factor Deficiency on Glutamate and Gamma-Aminobutyric Acid: Implications for Understanding Schizophrenia Pathophysiology.

ObjectiveDeficient brain-derived neurotrophic factor (BDNF) is one of the important mechanisms underlying the neuroplasticity abnormalities in schizophrenia. Aberration in BDNF signaling pathways directly or circuitously influences neurotransmitters like glutamate and gamma-aminobutyric acid (GABA). For the first time, this study attempts to construct and simulate the BDNF-neurotransmitter network in order to assess the effects of BDNF deficiency on glutamate and GABA.MethodsUsing CellDesigner, we modeled BDNF interactions with calcium influx via N-methyl-D-aspartate receptor (NMDAR)-Calmodulin activation; synthesis of GABA via cell cycle regulators protein kinase B, glycogen synthase kinase and β-catenin; transportation of glutamate and GABA. Steady state stability, perturbation time-course simulation and sensitivity analysis were performed in COPASI after assigning the kinetic functions, optimizing the unknown parameters using random search and genetic algorithm.ResultsStudy observations suggest that increased glutamate in hippocampus, similar to that seen in schizophrenia, could potentially be contributed by indirect pathway originated from BDNF. Deficient BDNF could suppress Glutamate decarboxylase 67-mediated GABA synthesis. Further, deficient BDNF corresponded to impaired transport via vesicular glutamate transporter, thereby further increasing the intracellular glutamate in GABAergic and glutamatergic cells. BDNF also altered calcium dependent neuroplasticity via NMDAR modulation. Sensitivity analysis showed that Calmodulin, cAMP response element-binding protein (CREB) and CREB regulated transcription coactivator-1 played significant role in this network.ConclusionThe study presents in silico quantitative model of biochemical network constituting the key signaling molecules implicated in schizophrenia pathogenesis. It provides mechanistic insights into putative contribution of deficient BNDF towards alterations in neurotransmitters and neuroplasticity that are consistent with current understanding of the disorder.

6 臼歯喪失ラットの学習記憶における海馬グルタミン酸変動(第511回 大阪歯科学会例会)

6 臼歯喪失ラットの学習記憶における海馬グルタミン酸変動(第511回 大阪歯科学会例会)

臼歯喪失ラットの学習記憶における海馬グルタミン酸変動(大阪歯科大学大学院歯学研究科博士(歯学)学位論文内容要旨および論文審査結果要旨の公表)

臼歯喪失ラットの学習記憶における海馬グルタミン酸変動(大阪歯科大学大学院歯学研究科博士(歯学)学位論文内容要旨および論文審査結果要旨の公表)

Functional dynamics of hippocampal glutamate during associative learning assessed with in vivo 1H functional magnetic resonance spectroscopy

fMRI has provided vibrant characterization of regional and network responses associated with associative learning and memory; however, their relationship to functional neurochemistry is unclear. Here, we introduce a novel application of in vivo proton functional magnetic resonance spectroscopy (1H fMRS) to investigate the dynamics of hippocampal glutamate during paired-associated learning and memory in healthy young adults. We show that the temporal dynamics of glutamate differed significantly during processes of memory consolidation and retrieval. Moreover, learning proficiency was predictive of the temporal dynamics of glutamate such that fast learners were characterized by a significant increase in glutamate levels early in learning, whereas this increase was only observed later in slow learners. The observed functional dynamics of glutamate provides a novel in vivo marker of brain function. Previously demonstrated N-methyl-D-aspartate (NMDA) receptor mediated synaptic plasticity during associative memory formation may be expressed in glutamate dynamics, which the novel application of 1H MRS is sensitive to. The novel application of 1H fMRS can provide highly innovative vistas for characterizing brain function in vivo, with significant implications for studying glutamatergic neurotransmission in health and disorders such as schizophrenia.

In vivo evaluation of the hippocampal glutamate, GABA and the BDNF levels associated with spatial memory performance in a rodent model of neuropathic pain

BackgroundPatients with chronic pain usually suffer from learning and memory impairment which may significantly decrease their quality of life. Despite laboratory and clinical studies, the mechanism underlying this memory impairment remains elusive. We evaluated the effect of chronic pain on the glutamate and GABA levels and BDNF expression in the CA1 region of hippocampus as a possible explanation for memory impairment related to neuropathic pain. MethodsIn this respect, 30 male rats were randomly allocated to 3 groups as control, sham and neuropathic. Neuropathic pain was induced by a chronic constriction injury of the sciatic nerve (CCI) and mechanical allodynia and the spatial memory was assessed using the Von Frey filaments and Morris water maze respectively. To determine the potential mechanisms, the in vivo extracellular levels of glutamate and γ-aminobutyric acid (GABA) were measured by microdialysis and the brain-derived neurotrophic factor (BDNF) expression was determined by using western blots technique in the hippocampus on days 14 and 21 post-CCI. ResultsWe showed that CCI impaired spatial learning and memory in Morris water maze (MWM) task. BDNF expression level and glutamate concentration significantly decreased in rats with chronic constriction injury of the sciatic nerve (P<0.001, F=7.3, F=23.23). In addition, GABA increased in hippocampal CA1 region (P<0.001, F=39.2) when the pain threshold was minimum. Nevertheless, these changes reversed while pain was relieved spontaneously. ConclusionChronic pain induced by constriction of the sciatic nerve impairs the spatial learning and memory function in rats. This effect exerts through the increase in GABA concentration and decrease in the glutamate and BDNF levels in the CA1 region of the hippocampus.

4.4 Hippocampal Glutamate and Functional Connectivity as Biomarkers of Treatment Response to Antipsychotic Medication

4.4 Hippocampal Glutamate and Functional Connectivity as Biomarkers of Treatment Response to Antipsychotic Medication