Hippocampal Neurotransmission Research Articles

Impulse noise exposure in rats causes cognitive deficits and changes in hippocampal neurotransmitter signaling and tau phosphorylation

Noise exposure has been characterized as a stressor, and its non-auditory effects on the central nervous system have been established both epidemiologically and experimentally. Little is known about the impact of impulse noise on the brain, however. In this study, we examined the effects of impulse noise stress on spatial learning and memory and on associated changes in the hippocampus. Rats were exposed to 20 sound impulses with a peak sound pressure of 165 dB and duration of 100 ms. Impulse noise stress led to a temporary decrease in cognitive function as evidenced by poor spatial memory in the Morris water maze (MWM). Effects of noise on the glutamate (Glu)–N-methyl- d-aspartic acid receptor (NMDAR) signaling system and hippocampal tau phosphorylation were investigated by high performance liquid chromatography, Western blotting, and immunohistochemistry. The concentrations of Glu and aspirate (Asp) in the hippocampus were increased at 30 min after exposure and remained elevated for the entire observation period (24 h), while the content of glycine (Gly) was stable for several hours following noise but also increased by 24 h after noise stress. Impulse noise stress also caused a significant increase in NMDAR 2B subunit (NR2B) expression and a two-phase increase in tau phosphorylation in hippocampus. Immunohistochemistry confirmed tau hyperphosphorylation in hippocampus that was most prominent in the dentate gyrus (DG) and CA1 region. These findings demonstrate that impulse noise stress impairs early spatial memory, possibly by disrupting Glu-NMDAR signaling and triggering aberrant tau hyperphosphorylation in hippocampus.

P.2.b.010 Dysfunctional hippocampal neurotransmission in the rat chronic mild stress model of depression

Stress exposure is one of the major risk factors of depression, but the mechanism is not understood. While some individuals show resilience to stress exposure, antidepressants only partially reduce stress-induced depression in both humans and rodents. Stress could dysregulate the remodeling of neuronal dendrites and spines in hippocampus while antidepressants could recover the deficiency induced by stress. EphA4 and its ligand ephrinA3 are critical in the remodeling of neuronal dendrites and spines, but the relationship between ephrinA3/EphA4, stress-induced depression and antidepressants treatment is largely unknown. Based on a rat chronic unpredicted mild stress (CUMS) model, we investigated ephrinA3/EphA4 expression in stress susceptibility, stress resilience, treatment response and treatment resistance in rats. CUMS led to downregulation of EphA4 expression and upregulation of ephrinA3 expression in the hippocampus of stress-susceptible rats, but not in stress-resilient rats. Dysregulated EphA4 and ephrinA3 can be rescued by fluoxetine administration in drug responders, but not in fluoxetine resistant rats. These data provide insights into the potential role of EphA4 and ephrinA3 after stressor exposure, stress adaptation, fluoxetine response and drug treatment refraction.

Chronically saturating levels of endogenous glycine disrupt glutamatergic neurotransmission and enhance synaptogenesis in the CA1 region of mouse hippocampus

Glycine serves a dual role in neurotransmission. It is the primary inhibitory neurotransmitter in the spinal cord and brain stem and is also an obligatory coagonist at the excitatory glutamate, N-methyl-D-aspartate receptor (NMDAR). Therefore, the postsynaptic action of glycine should be strongly regulated to maintain a balance between its inhibitory and excitatory inputs. The glycine concentration at the synapse is tightly regulated by two types of glycine transporters, GlyT1 and GlyT2, located on nerve terminals or astrocytes. Genetic studies demonstrated that homozygous (GlyT1-/-) newborn mice display severe sensorimotor deficits characterized by lethargy, hypotonia, and hyporesponsivity to tactile stimuli and ultimately die in their first postnatal day. These symptoms are similar to those associated with the human disease glycine encephalopathy in which there is a high level of glycine in cerebrospinal fluid of affected individuals. The purpose of this investigation is to determine the impact of chronically high concentrations of endogenous glycine on glutamatergic neurotransmission during postnatal development using an in vivo mouse model (GlyT1+/-). The results of our study indicate the following; that compared with wild-type mice, CA1 pyramidal neurons from mutants display significant disruptions in hippocampal glutamatergic neurotransmission, as suggested by a faster kinetic of NMDAR excitatory postsynaptic currents, a lower reduction of the amplitude of NMDAR excitatory postsynaptic currents by ifenprodil, no difference in protein expression for NR2A and NR2B but a higher protein expression for PSD-95, an increase in their number of synapses and finally, enhanced neuronal excitability.

Enhancement of serotonergic and noradrenergic neurotransmission in the rat hippocampus by sustained administration of bupropion

Previous studies reported that bupropion, an effective antidepressant, exerts modulatory actions on serotonin (5-HT) and norepinephrine (NE) neurons. This study examined effects of bupropion administration on 5-HT and NE neurotransmission in hippocampus. Electrophysiological recordings were obtained from anesthetized Sprague-Dawley rats. Subcutaneously implanted minipumps delivered saline or bupropion (30 mg/kg/day) for 2 and 14 days. Although sustained bupropion administration did not alter the sensitivity of 5-HT(1A) and α₂-adrenergic receptors, the tonic activation of postsynaptic 5-HT(1A) receptors by endogenous 5-HT was enhanced in 14-day bupropion-treated rats to a greater extent than in the 2-day and control rats, as revealed by the greater disinhibitory action of the 5-HT(1A) antagonist WAY-100635 on hippocampus pyramidal neurons. The function of terminal 5-HT(1B) autoreceptors was not changed as determined by the unaltered effectiveness of different frequencies of stimulation of the ascending 5-HT fibers. The function of α₂-adrenergic receptors on 5-HT terminals was, however, diminished, as indicated by the lesser effect of the α₂-adrenoceptor agonist clonidine. Tonic activation of postsynaptic α₂- and α₁-adrenoceptors by endogenous NE was also increased in 14-day bupropion-treated rats, as indicated by the greater effect of the α₂- and α₁-adrenoceptor antagonists idazoxan and prazosin, respectively, on pyramidal firing. The function of terminal α₂-adrenergic autoreceptors was attenuated since increasing frequency of stimulation of the ascending NE pathway produced a lesser degree of suppression of pyramidal neurons in rats administered bupropion than the control. Enhancement of 5-HT and NE transmissions in hippocampus by prolonged bupropion may account for its effectiveness in major depression.

Increased hippocampal noradrenaline is a biomarker for efficacy of vagus nerve stimulation in a limbic seizure model

Vagus nerve stimulation (VNS) is an effective adjunctive treatment for medically refractory epilepsy. In this study, we measured VNS-induced changes in hippocampal neurotransmitter levels and determined their potential involvement in the anticonvulsive action of VNS, to elucidate the mechanism of action responsible for the seizure suppressing effect of VNS in an animal model for limbic seizures. We used in vivo intracerebral microdialysis to measure VNS-induced changes in hippocampal extracellular concentrations of noradrenaline, dopamine, serotonin and GABA in freely moving, male Wistar rats. During the same experiment, the effect of VNS on pilocarpine-induced limbic seizures was assessed using video-EEG monitoring. The involvement of VNS-induced increases in hippocampal noradrenaline in the mechanims of action of VNS was evaluated by blocking hippocampal α(2)-receptors. VNS produced a significant increase in hippocampal noradrenaline concentration (69 ± 16% above baseline levels). VNS also increased the latency between pilocarpine infusion and the onset of epileptiform discharges, and reduced the duration and severity of pilocarpine-induced limbic seizures. A strong positive correlation was found between the noradrenergic and anticonvulsive effects of VNS. Blockade of hippocampal α(2 -receptors reversed the seizure-suppressing effect of VNS. VNS induces increases in extracellular hippocampal noradrenaline, which are at least partly responsible for its seizure-suppressing effect in a model for limbic seizures, and constitute a potential biomarker for the efficacy of VNS in temporal lobe epilepsy.

An Emerging Role for TARPs in Neuropsychiatric Disorders

The discovery of glutamate as the principal excitatory neurotransmitter in brain was followed by the identification and molecular cloning of the ionotropic glutamate receptor family, which comprises NMDA, AMPA, and kainate receptors. The AMPA receptor subfamily mediates fast synaptic neurotransmission important to diverse sensory, behavioral, and cognitive processes, including learning and memory. However, excessive AMPA receptor activity and subsequent excitotoxicity underlie central nervous system disorders ranging from stroke to epilepsy. It was hypothesized that the development of AMPA receptor antagonists to dampen aberrant neurotransmission would provide treatments for neurological illnesses. However, clinical trials have shown side effects for these antagonists and suggested a need for greater selectivity. A seminal finding in AMPA receptor biology and neurotransmission was the discovery of stargazin, the protein mutated in stargazer mice, which show absence epilepsy and cerebellar ataxia. Cell biological and physiological studies showed that stargazin is an AMPA receptor auxiliary subunit and controls receptor trafficking, gating, and pharmacology. Subsequent studies have identified a family of related transmembrane AMPA receptor regulator proteins (TARPs). TARPs comprise γ-2 (stargazin), -3, -4, -5, -7, and -8 subunits, which are discretely distributed in specific neuronal and glial populations throughout the brain. Studies involving γ-8 knockout mice, which exhibit deficiencies in hippocampal neurotransmission, underscore the importance of TARPs both in region-specific control of AMPA receptor signaling, and in neurological disease—hippocampal excitotoxicity elicited by the AMPA receptor partial agonist, kainate, is abrogated in γ-8 knockout mice (Tomita et al, 2007). Neuropsychiatric conditions such as schizophrenia, depression, and bipolar disorder are severe, multifactorial brain illnesses of mood, cognition, and behavior whose etiologies remain uncertain. Molecular analyses have found abnormal expression for key components of glutamatergic neurotransmission, including TARPs. Increased and decreased stargazin mRNA expression has been documented in post-mortem schizophrenic and major depressive disorder brains, respectively (Beneyto and Meador-Woodruff, 2006). Silberberg et al (2008) found certain CACNG2 (the gene that encodes stargazin) allelic polymorphisms are associated with improved response to lithium, the classical treatment for bipolar disorder. Furthermore, chronic treatment with the antidepressants desipramine and paroxetine increased AMPA receptor association with stargazin in rat hippocampus (Martinez-Turrillas et al, 2007). Patients with bipolar disorder or schizophrenia have exhibited decreased CACNG2 DNA copy number (Wilson et al, 2006). Yet, increased stargazin mRNA expression has been found in the dorsolateral prefrontal cortex of brains from bipolar disorder patients suggesting a potential regio-specific action for stargazin in this disorder (Silberberg et al, 2008). Furthermore, the PDE 11A knockout mouse, which shows multiple psychiatric illness-related phenotypes, possessed decreased hippocampal expression of both γ-2 and -8 proteins (Kelly et al, 2010). Recent research into neuropsychiatric illnesses has shown an emerging pathological role for TARPs. As TARPs are differentially localized in neuron pathways, targeting individual isoforms may enable selective modulation of specific brain circuits without globally affecting synaptic transmission. However, the feasibility of uniquely targeting specific AMPA receptor complexes has not yet been established.

Effects of Chinese herbal medicine Xiaoyao Powder on monoamine neurotransmitters in hippocampus of rats with postpartum depression

To investigate the effects of Xiaoyao Powder, a compound traditional Chinese herbal medicine for treatment of depression, on monoamine neurotransmitters in hippocampus of rats with postpartum depression (PPD). Ovariectomized Sprague-Dawley rats were randomly divided into 4 groups: control group, untreated group, fluoxetine hydrochloride group and Xiaoyao Powder group. Except for the control group, the rats in the other 3 groups were injected subcutaneously with estrogen for 23 successive days to induce the "pregnancy" state. In the next 30 successive days, rats were given test drugs respectively and the concentrations of noradrenaline (NE), dopamine (DA), 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) in hippocampus were measured by enzyme-linked immunosorbent assay (ELISA). PPD was induced in rats of untreated group, and compared with rats of control group, the concentrations of NE, DA and 5-HT in the hippocampus significantly reduced (P<0.01), while the concentration of 5-HIAA significantly increased (P<0.01). Xiaoyao Powder treatment significantly improved the behavior indexes and levels of monoamine neurotransmitters in hippocampus (P<0.01). Xiaoyao Powder and fluoxetine hydrochloride produced similar effects in rats with PPD. Xiaoyao Powder produces an antidepression effect in rats by regulating the levels of monoamine neurotransmitters in hippocampus.

Effect of Kangshuai Yizhi Formula I (抗衰益智方 I) on learning and memory dysfunction induced by scopolamine in mice

To evaluate the improvement of Kangshuai Yizhi Formula I ( I, KYF I) on: the learning and memory dysfunction in mice, and on the mechanism of the hippocampal cholinergic system and the nervous system of monoamine which are closely related to learning and memory function. Mice: in the low-, middle-, and high-dose KYF I groups were given low-, middle-, and high-dose KYF, respectively, by gastrogavage for 35 successive days. Animals in the control group and the model group were treated with distilled water. The acute learning and memory dysfunction model was established by injection of scopolamine from day 31, and Morris water maze was used to assess the behavior performance of scopolamine-induced model mice for five days. The activities of acetylcholinesterase (AChE), choline acetyl transferase (ChaT) and the content of monoamine neurotransmitters in hippocampus were measured. The activity of monoamine oxidase (MAO) in hippocampus and serum was also detected. (1) Compared with the control group, the: mean escape latency was shortened, and the frequency across the platform and the staying time at the platform area on the 5th day were decreased in the model group by Morris water maze test. The activities of AChE and MAO were increased, and the ChaT activity and monoamine neurotransmitter content were decreased as well. (2) The escape latency for 4 days in the low-, middle-, and high-dose KYF I groups was significantly shortened than that in the model group, with the shortest latency in the high-dose KYF I group (P<0.05, P<0.01). The frequency across the platform was significantly increased and the staying time at the platform was significantly prolonged in the middle- and high-dose KYF I groups (P<0.05, P<0.01). (3) As compared with the model group, the activity of ChaT and the content of monoamine neurotransmitters in the hippocampus were significantly increased, and the activities of AchE and MAO were significantly decreased in the hippocampus in the high-dose KYF I group (P<0.01). High-dose KYF I can significantly improve the learning and memory dysfunction: induced by scopolamine in mice. Its mechanism may be related to improving the central cholinergic system and regulating the hippocampal monoamine neurotransmitters.

Moderate Hypogonadism Enhances Hippocampal Neurotransmission, Augments Memory and Learning and Modulates Neurogenesis in Adult Male Rats.

Moderate Hypogonadism Enhances Hippocampal Neurotransmission, Augments Memory and Learning and Modulates Neurogenesis in Adult Male Rats.

Aging alters the expression of neurotransmission‐regulating proteins in the hippocampal synaptoproteome

Decreased cognitive performance reduces independence and quality of life for aging individuals. Healthy brain aging does not involve significant neuronal loss, but little is known about the effects of aging at synaptic terminals. Age-related cognitive decline likely reflects the manifestation of dysregulated synaptic function and ineffective neurotransmission. In this study, hippocampal synaptosomes were enriched from young-adult (3 months), adult (12 months), and aged (26 months) Fischer 344 x Brown Norway rats, and quantitative alterations in the synaptoproteome were examined by 2-DIGE and MS/MS. Bioinformatic analysis of differentially expressed proteins identified a significant effect of aging on a network of neurotransmission-regulating proteins. Specifically, altered expression of DNM1, HPCA, PSD95, SNAP25, STX1, SYN1, SYN2, SYP, and VAMP2 was confirmed by immunoblotting. 14-3-3 isoforms identified in the proteomic analysis were also confirmed as a result of their implication in the regulation of the synaptic vesicle cycle and neurotransmission modulation. The findings of this study demonstrate a coordinated down-regulation of neurotransmission-regulating proteins that suggests an age-based deterioration of hippocampal neurotransmission occurring between adulthood and advanced age. Altered synaptic protein expression may decrease stimulus-induced neurotransmission and vesicle replenishment during prolonged or intense stimulation, which are necessary for learning and the formation and perseverance of memory.

Learning discloses abnormal structural and functional plasticity at hippocampal synapses in the APP23 mouse model of Alzheimer's disease

B6-Tg/Thy1APP23Sdz (APP23) mutant mice exhibit neurohistological hallmarks of Alzheimer's disease but show intact basal hippocampal neurotransmission and synaptic plasticity. Here, we examine whether spatial learning differently modifies the structural and electrophysiological properties of hippocampal synapses in APP23 and wild-type mice. While no genotypic difference was found in the pseudotrained mice, training elicited a stronger increase in spine density and a more rapid decay of long-term potentiation (LTP) in APP23 mutants. Thus, learning discloses mutation-related abnormalities regarding dendritic spine formation and LTP persistence, thereby suggesting that although unaltered in naïve synapses, plasticity becomes defective at the time it comes into play.

Zinc and glutamine improve brain development in suckling mice subjected to early postnatal malnutrition

Objective The effect of zinc and glutamine on brain development was investigated during the lactation period in Swiss mice. Methods Malnutrition was induced by clustering the litter size from 6–7 pups/dam (nourished control) to 12–14 pups/dam (undernourished control) following birth. Undernourished groups received daily supplementation with glutamine by subcutaneous injections starting at day 2 and continuing until day 14. Glutamine (100 mM, 40–80 μL) was used for morphological and behavioral studies. Zinc acetate was added in the drinking water (500 mg/L) to the lactating dams. Synaptophysin and myelin basic protein brain expressions were evaluated by immunoblot. Zinc serum and brain levels and hippocampal neurotransmitters were also evaluated. Results Zinc with or without glutamine improved weight gain as compared to untreated, undernourished controls. In addition, zinc supplementation improved cliff avoidance and head position during swim behaviors especially on days 9 and 10. Using design-based stereological methods, we found a significant increase in the volume of CA1 neuronal cells in undernourished control mice, which was not seen in mice receiving zinc or glutamine alone or in combination. Undernourished mice given glutamine showed increased CA1 layer volume as compared with the other groups, consistent with the trend toward increased number of neurons. Brain zinc levels were increased in the nourished and undernourished-glutamine treated mice as compared to the undernourished controls on day 7. Undernourished glutamine-treated mice showed increased hippocampal gamma-aminobutyric acid and synaptophysin levels on day 14. Conclusion We conclude that glutamine or zinc protects against malnutrition-induced brain developmental impairments.

Involvement of the AT1 receptor subtype in the effects of angiotensin IV and LVV‐haemorphin 7 on hippocampal neurotransmitter levels and spatial working memory

Intracerebroventricular (i.c.v.) administration of angiotensin IV (Ang IV) or Leu-Val-Val-haemorphin 7 (LVV-H7) improves memory performance in normal rats and reverses memory deficits in rat models for cognitive impairment. These memory effects were believed to be mediated via the putative 'AT4 receptor'. However, this binding site was identified as insulin-regulated aminopeptidase (IRAP). Correspondingly, Ang IV and LVV-H7 were characterised as IRAP inhibitors. This study investigates whether and how IRAP may be involved in the central effects of Ang IV and LVV-H7. We determined the effects of i.c.v. administration of Ang IV or LVV-H7 on hippocampal neurotransmitter levels using microdialysis in rats. We observed that Ang IV modulates hippocampal acetylcholine levels, whereas LVV-H7 does not. This discrepancy was reflected in the observation that Ang IV binds with micromolar affinity to the AT1 receptor whereas no binding affinity was observed for LVV-H7. Correspondingly, we demonstrated that the AT1 receptor is involved in the effects of Ang IV on hippocampal neurotransmitter levels and on spatial working memory in a plus maze spontaneous alternation task. However, the AT1 receptor was not involved in the spatial memory facilitating effect of LVV-H7. Finally, we demonstrated that Ang IV did not diffuse to the hippocampus following i.c.v. injection, suggesting an extrahippocampal site of action. We propose that AT1 receptors are implicated in the neurochemical and cognitive effects of Ang IV, whereas LVV-H7 may mediate its effects via IRAP.

Disruption of ClC-2 expression is associated with progressive neurodegeneration in aging mice

Heterozygous mutations in ClC-2 have been associated in rare cases with increased susceptibility to generalized, idiopathic epilepsy. Initially, it was hypothesized that mutations in ClC-2 may be associated with epilepsy due to a direct role for ClC-2 in the modification of hippocampal neuronal excitability. However, the absence of an overt seizure-susceptibility phenotype in young ClC-2 knockout (KO) mice rendered this hypothesis- implausible. A recent study of older ClC-2 KO mice (>6 months) revealed abnormalities in the myelin of central axons and a subtle defect in the neuronal function in the central auditory pathway. These findings prompted us to re-examine hippocampal neuron morphology and excitability in older ClC-2 KO mice. Interestingly, electrocorticographic recordings obtained in older mice revealed spontaneous interictal spikes which are a marker of perturbed hippocampal neurotransmission with a resultant increase in excitation. This electrophysiological defect was associated with astrocyte activation and evidence of neuronal degeneration in the CA3 region of the hippocampus of these older mice. Together, these findings raise the possibility that ClC-2 expression plays a subtle neuroprotective role in the aging hippocampus.

Pravastatin treatment causes a shift in the balance of hippocampal neurotransmitter binding densities towards inhibition

Since pravastatin, a HMG-CoA reductase inhibitor, has recently been shown to reduce infarct volumes and glutamate release in a rat model of ischemic stroke, the aim of the present study was to investigate whether this neuroprotective effect may be due to a modulation of excitatory and inhibitory neurotransmitter receptors. Therefore, Wistar rats were treated six times in 4 days with pravastatin or saline and allowed to survive for 6 hours or 5 days ( n = 10 per time point and group), respectively. Using quantitative receptor autoradiography, ligand binding densities of [ 3H]MK-801, [ 3H]AMPA, and [ 3H]muscimol for labeling of NMDA, AMPA, and GABA A receptors were analyzed in sensorimotor cortices Par1 and Par2, the striatum, and the hippocampus. Statin therapy induced complex alterations of ligand binding densities in different brain regions. Labeling of NMDA receptors was significantly increased in Par2, both after 6 hours and 5 days, respectively. Within the striatum, AMPA as well as GABA A receptor binding values were significantly increased on day 5. Furthermore, a marked and significant increase of [ 3H]muscimol ligand binding to GABA A receptors throughout all hippocampal subfields was seen after 6 hours. This complexity could easily be unraveled when focusing on the balance between excitatory glutamate and inhibitory GABA A receptors, in which case only the increase of hippocampal [ 3H]muscimol ligand binding 6 hours after the first application of pravastatin was accompanied by a net shift towards inhibition. Consequently, our data suggest an additional regulatory pathway induced by statins, namely modification of the abundance of excitatory and inhibitory neurotransmitter receptors.

Maternal social stress during late pregnancy affects hypothalamic-pituitary-adrenal function and brain neurotransmitter systems in pig offspring

Maternal stress in pregnant sows may induce long-lasting alterations in the behavior, physiology, and immunity of their offspring. The aim of the present study was to investigate the consequences of repeated social stress during late gestation on determinants of the hypothalamic–pituitary–adrenal axis and on hippocampal neurotransmitter profiles in pig offspring. All pregnant gilts were housed in pairs. Each Stress gilt was mixed with an unfamiliar gilt twice a week between days 77 and 105 of gestation (n = 18). Control gilts were housed in stable pairs over the same period (n = 18). Plasma cortisol and corticosteroid binding globulin (CBG) were measured in 1 male and 1 female per litter in a basal situation on postnatal days (PND) 4, 26, and 60 and in a stressful situation at PND 28 (2 d after weaning) and 62 (2 d after relocation to a new building). Prenatal stress had no effect on plasma cortisol, but it decreased CBG at PND 26. Brain and adrenals were collected from 1 female per litter after weaning or relocation at PND 28 and PND 62. Adrenals were additionally collected at PND 4. Glucocorticoid receptor binding in the hippocampus and hypothalamus was not affected by prenatal treatment. However, prenatal stress increased the expression of 11β-hydroxysteroid dehydrogenase type 1 mRNA in the hippocampus after weaning ( P < 0.05) and after relocation ( P = 0.08). In addition, prenatally stressed piglets showed an increased 5-hydroxyindole-3-acetic acid to 5-hydroxytryptamine ratio in the hippocampus after weaning and increased hippocampal c-fos mRNA expression and noradrenaline concentration after relocation ( P < 0.05). Prenatal stress also increased the relative adrenal weight at PND 4 and the cell density in the cortex and the medulla at PND 28, whereas no difference was found for activities of catecholamine-synthesising enzymes in the medulla. Overall, our data indicate that repeated social stress during pregnancy has long-lasting consequences on hypothalamic–pituitary–adrenal axis and hippocampal neurotransmitter activity in the offspring of pigs.

S.20.04 Consequences of altered BDNF protein levels on hippocampal serotonin neurotransmission and behaviour

S.20.04 Consequences of altered BDNF protein levels on hippocampal serotonin neurotransmission and behaviour

Long-Term Reduction of Hippocampal Brain-Derived Neurotrophic Factor Activity After Fetal-Neonatal Iron Deficiency in Adult Rats

Fetal-neonatal iron deficiency acutely alters hippocampal biochemistry, neural morphology, and electrophysiology accompanied by a downregulation of brain-derived neurotrophic factor (BDNF). These changes provide a cellular and molecular basis for observed short-term learning and memory impairments. However, the etiology of residual, long-term hippocampal neurotransmission abnormalities and learning impairments after treatment remain unclear. Because BDNF modulates learning and memory, we assessed its expression in 65-d-old formerly iron deficient (FID) male rats that had been iron deficient during the fetal-neonatal period and treated with iron since postnatal day 7. BDNF-III and -IV mRNAs and BDNF protein expression remained down-regulated in FID rats when compared with the always iron-sufficient rats. Expressions of BDNF activity-dependent downstream targets (3-hydroxy-3-methylglutaryl CoA reductase and immediate early genes c-fos, early growth response gene 1 and 2) were reduced in FID rats. In turn, hippocampal expressions of direct targets of early-growth response genes, including hypoxia-inducible factor 1, dual-specificity phosphatase 4, IGF 2, and myelin basic protein were also diminished in FID rats. Collectively, fetal-neonatal iron deficiency lowers hippocampal BDNF expression and function beyond the period of iron deficiency. These findings may underlie the persistence of learning deficits seen after fetal-neonatal iron deficiency.

Phoneutria spider toxins block ischemia‐induced glutamate release, neuronal death, and loss of neurotransmission in hippocampus

The aim of this study was to investigate the effect of spider toxins on brain injury induced by oxygen deprivation and low glucose (ODLG) insult on slices of rat hippocampus. After ODLG insult cell viabilility in hippocampal slices was assessed by confocal microscopy and epifluorescence using the live/dead kit containing calcein-AM and ethidium homodimer and CA1 population spike amplitude recording during stimulation of Schaffer collateral fibers. Spider toxins Tx3-3 or Tx3-4 and conus toxins, omega-conotoxin GVIA or omega-conotoxin MVIIC are calcium channel blockers and protected against neuronal damage in slices subjected to ODLG insult. Confocal imaging of CA1 region of rat hippocampal slices subject to ischemic insult treated with Tx3-3, Tx3-4, omega-conotoxin GVIA or omega-conotoxin MVIIC showed a decrease in cell death that amounted to 68 +/- 4.2%, 77 +/- 3.8%, 32 +/- 2.3%, and 46 +/- 2.9%, respectively. This neuroprotective effect of Tx3-4 was corroborated by eletrophysiological recordings of population spikes amplitudes in CA1. The neuroprotection promoted on hippocampal slices by Tx3-3 or Tx3-4 was also observed when the toxins were applied 10, 20, 30, 60, 90, or 120 min after induction of the ODLG injury. During the ischemic insult, glutamate release from slices was increased by 71% (from 7.0 +/- 0.3 nM/mg of protein control slices not subjected to ischemia to 12 +/- 0.4 nM/mg of protein in slices exposed to ischemia). Tx3-3, Tx3-4, omega-conotoxin GVIA or omega-conotoxin MVIIC inhibited the ischemia-induced increase on glutamate release by 54, 72, 60, and 70%, respectively. Thus Tx3-3 and Tx3-4 provided robust ischemic neuroprotection showing potential as a novel class of agent that exerts neuroprotection in an in vitro model of brain ischemia.

Strain Differences in Extracellular Amino Acid Neurotransmitter Levels in the Hippocampi of Major Histocompatibility Complex Congenic Mice in Response to Toluene Exposure

Objective: The aim of the present study was to investigate the possible role of the major histocompatibility complex locus in neurotransmitter systems in the mouse hippocampus following toluene exposure. Methods: We compared the changes in toluene-induced extracellular amino acid neurotransmitter levels in the hippocampi of 2 strains of male congenic mice, C57BL/10 (H-2^b) and B10.BR/Sg (H-2^k). In vivo microdialysis was performed in each freely moving mouse after a single intraperitoneal injection of toluene (300 mg/kg), and neurotransmitters in the hippocampal microdialysates were measured using high-performance liquid chromatography. Results: The basal extracelluar glutamate and glycine levels in the hippocampi of the C57BL mice were significantly higher than those in the B10.BR mice. However, the basal extracellular taurine levels in the hippocampi of the C57BL mice were significantly lower than those in the B10.BR mice. Although no changes in the glutamate levels were observed after toluene injection in either strain, the glycine levels increased significantly after toluene injection in the C57BL mice. On the other hand, significantly lower taurine levels were observed after toluene injection in both strains of mice. Conclusions: Our data demonstrate the existence of a relationship between H-2 haplotypes and hippocampal neurotransmitter levels in mice.