Alterations in synaptic transmission and plasticity in area CA1 of adult hippocampus following developmental hypothyroidism

Transient reductions in thyroid hormone during critical periods of brain development can have devastating and irreversible effects on neurological function. The hippocampus is a brain region sensitive to thyroid hormones and is a necessary substrate for some forms of learning and memory. Subregions within the hippocampus display distinct ontogenetic profiles and have shown differential vulnerability to some indices of thyrotoxic insult. Synaptic function can be readily assessed in the hippocampus, yet little information exists on the consequences of early thyroid hormone insufficiency on the neurophysiological integrity of this structure. Previous work has examined the long-term consequences of perinatal hypothyroidism on neurophysiology of the dentate gyrus of the hippocampal formation. The current study reveals that alterations in synaptic function also exist in area CA1, and some differences in the pattern of effects are evident between the two hippocampal subfields. Developing rats were transiently exposed to the thyrotoxicant, propylthiouracil (PTU; 0 or 15 ppm), through the drinking water of pregnant dams beginning on gestational day 18. This regimen markedly reduced circulating levels of thyroid hormones and stunted pup growth. PTU exposure was terminated on postnatal day (PN) 21 and electrophysiological assessments were conducted by recording field potentials in area CA1 of hippocampal slices derived from adult male offspring. Synaptic transmission, short-term, and long-term synaptic plasticity were assessed. Consistent with observations in the dentate gyrus, somatic population spike amplitudes were reduced in assessments of baseline synaptic transmission of slices from PTU-exposed animals. No differences were identified in excitatory postsynaptic potentials (EPSP). Short-term plasticity of the EPSP as indexed by paired pulse facilitation was markedly impaired by PTU exposure. Long-term potentiation (LTP) of the population spike was enhanced, consistent with findings in dentate gyrus, but no change in EPSP LTP was detected. Perturbations in synaptic function in the hippocampus of adult rats transiently exposed to a period of hormone insufficiency during the perinatal period are likely to contribute to cognitive deficits associated with developmental hypothyroidism.     

Lack of central effects of peripherally administered adenosine A(1) agonists on synaptic transmission in the rat hippocampus

Peripheral administration of adenosine A(1) receptor selective agonists is generally thought to protect the hippocampus against ischemic damage via central actions. We examined the effects of two peripherally administered A(1) agonists, cyclohexyladenosine (CHA) and adenosine amine congener (ADAC), on synaptic transmission in the hippocampus and on indices of cardiovascular function. We conclude that the permeability of these agonists is not sufficient to result in concentrations necessary to activate central adenosine A(1) receptors within the hippocampus.     

Hydroxylamine blocks adenosine A1 receptor-mediated inhibition of synaptic transmission in rat hippocampus

The nitric oxide donor hydroxylamine (NH₂OH) induced a transient depression of the evoked synaptic potential recorded in the rat hippocampal CA1 region. This depression was abolished with an adenosine A₁ antagonist, 8-cyclopentyltheophylline. In addition, hydroxylamine reversed adenosine A₁ receptor-mediated inhibition of the evoked population spike, the fEPSP and the intracellularly recorded EPSP. The inhibitory modulation of adenosine A₁ receptor activation by hydroxylamine suggests the presence of a potent endogenous regulatory site.     

Adenosine A2b receptors control A1 receptor‐mediated inhibition of synaptic transmission in the mouse hippocampus

Adenosine is a neuromodulator mostly acting through A₁ (inhibitory) and A_2A (excitatory) receptors in the brain. A_2B receptors (A_2BR) are G_s/q‐protein‐coupled receptors with low expression in the brain. As A_2BR function is largely unknown, we have now explored their role in the mouse hippocampus. We performed electrophysiological extracellular recordings in mouse hippocampal slices, and immunological analysis of nerve terminals and glutamate release in hippocampal slices and synaptosomes. Additionally, A_2BR‐knockout (A_2BR‐KO) and C57/BL6 mice were submitted to a behavioural test battery (open field, elevated plus‐maze, Y‐maze). The A_2BR agonist BAY60‐6583 (300 nm ) decreased the paired‐pulse stimulation ratio, an effect prevented by the A_2BR antagonist MRS 1754 (200 nM) and abrogated in A_2BR‐KO mice. Accordingly, A_2BR immunoreactivity was present in 73 ± 5% of glutamatergic nerve terminals, i.e. those immunopositive for vesicular glutamate transporters. Furthermore, BAY 60‐6583 attenuated the A₁R control of synaptic transmission, both the A₁R inhibition caused by 2‐chloroadenosine (0.1–1 μm ) and the disinhibition caused by the A₁R antagonist DPCPX (100 nm ), both effects prevented by MRS 1754 and abrogated in A_2BR‐KO mice. BAY 60‐6583 decreased glutamate release in slices and also attenuated the A₁R inhibition (CPA 100 nm ). A_2BR‐KO mice displayed a modified exploratory behaviour with an increased time in the central areas of the open field, elevated plus‐maze and the Y‐maze and no alteration of locomotion, anxiety or working memory. We conclude that A_2BR are present in hippocampal glutamatergic terminals where they counteract the predominant A₁R‐mediated inhibition of synaptic transmission, impacting on exploratory behaviour.     

The role of adiponectin receptors in the regulation of synaptic transmission in the hippocampus

In the last two decades adiponectin, member of the adipokines family, gained attention because of its unique antidiabetic effects. However, the presence in the brain of adiponectin receptors and adiponectin itself raised interest because of the possible association with neuropsychiatric diseases. Indeed, clinical studies found altered concentration of adiponectin both in plasma and cerebrospinal fluid in several pathologies including depression, multiple sclerosis, Alzheimer's disease and stroke. Moreover, recent preclinical studies also suggest its involvement in different physiological functions. Despite this evidence very few studies attempted to elucidate the functional role of adiponectin at the synapse. To address this question, here we investigated the effect of Adiporon, an agonist of both adiponectin receptors on synaptic transmission and LTP at Schaffer‐collateral CA1 pathway. Surprisingly, increasing concentration of Adiporon correlated with lower CA1–LTP levels and paired‐pulse ratio, whereas basal transmission was always preserved. Collectively, our data show that the adiponectin system, beyond its involvement in metabolic diseases, plays also a critical role in synaptic activity thereby representing a putative target for the treatment of synaptic pathologies.     

GABAB受体对大鼠海马CA1区锥体细胞突触传递的作用

目的研究激活GABA_B受体对大鼠海马CA1区锥体细胞突触传递的影响。方法对成年大鼠海马脑片CA1区锥体细胞采用“盲法”全细胞电压钳记录,分别检测和分析巴氯芬(10μmol/L)对自发性的兴奋性突触后电流(EPSCs)和抑制性突触后电流(IPSCs)的影响。结果巴氯芬可显著降低符氨酸能EPSCs和γ-氨基丁酸能IPSCs的频率(P＜0．01),各自达58%±7%(n=17)和42%±10%(n=15),而对它们的幅度无显著性影响。结论巴氯芬对海马CA1区锥体细胞EPSCs和IPSCs的抑制作用属于突触前抑制,推测GABA_B受体所介导的这种抑制作用对CA1区神经元兴奋性的传出具有抑制作用,从而对癫痫的产生有控制作用。     

Ontogeny of synaptic transmission in the rat hippocampus

Electrophysiological characteristics of the hippocampal slices of juvenile (14-27 days) or young (36-40 days) Wistar rats have been compared. In the juvenile rats measurements were taken daily, from postnatal day (PN) 14 to PN27. Input-output curves were used to quantify the ontogeny of excitatory processes. The dynamic of population spike (PS) maturation was not even during the investigated postnatal period. After day 19 transient decrease of PS amplitude was observed until day 22. There were also some differences between the shape of input-output curves from the slices of rats of different ages. In general, PS was saturated at lower intensities in younger animals. The slices from 19-day-old rats did not display saturated input-output curve with 2-20 V stimuli intensities. But input-output curves on PN20-22 were rather similar to that obtained before PN19. The periods of gradual increase and subsequent decrease of PS amplitudes during early ontogeny correlate with the appearance of certain forms of behaviour. This fact suggests that hippocampal PS amplitude depression may be relevant functionally.     

Action of phencyclidine on synaptic transmission in the hippocampus

A neurophysiological investigation of the effects of phencyclidine (PCP) and ketamine on synaptic transmission was carried out at the level of two excitatory connections of the hippocampal formation: the interhippocampal projections from contralateral CA3 (cCA3) to CA1 and the entorhino-dentate pathway.In urethane-anesthetized rats PCP i.v. produced a moderate depression of the population EPSP elicited in the stratum radiatum of CA1 by cCA3 stimulations (16–40%) and a large decrease (up to 97%) of the amplitude of the corresponding population spike recorded at the level of the CA1 pyramidal cell bodies (ED₅₀:1.83 mg/kg).Single-unit analysis of CA1 pyramidal cell activation triggered by cCA3 stimulations indicated that i.v. PCP did not decrease the amplitude of individual action potentials suggesting that the decrease in the size of the population spike was due to a decrease in the number of CA1 pyramidal cells activated by the stimulus. Moreover, PCP administered i.v. in the same dose range (0.6-4.0 mg/kg) reduced the maintained activity of CA1 pyramidal cells and their excitation by iontophoretically applied glutamate or ACh.Similar effects on both field potentials and single-unit activity in the CA1 area were also observed following the administration of larger i.v. doses of ketamine (ED₅₀: 7.2 mg/kg), but the effects of the latter drug were of considerably shorter duration than those of PCP.     

Vasoactive intestinal peptide acts via multiple signal pathways to regulate hippocampal NMDA receptors and synaptic transmission

Vasoactive intestinal peptide (VIP) is a 28‐amino acid peptide, which belongs to a superfamily of structurally related peptide hormones including pituitary adenylate cyclase‐activating polypeptide (PACAP). Although several studies have identified the involvement of PACAP in learning and memory, little work has been done to investigate such a role for VIP. At least three receptors for VIP have been identified including the PACAP receptor (PAC1‐R) and the two VIP receptors (VPAC receptors). VIP can activate the PAC1‐R only if it is used at relatively high concentrations (e.g., 100 nM); however, at lower concentrations (e.g., 1 nM) it is selective for the VPAC receptors. Our lab has showed that PAC1‐R activation signals through PKC/CAKβ/Src pathway to regulate NMDA receptors; however, there is little known about the potential regulation of NMDA receptors by VPAC receptors. Our studies demonstrated that application of 1 nM VIP enhanced NMDA currents by stimulating the VPAC receptors as the effect was blocked by VPAC receptor antagonist [Ac‐Tyr¹, D‐Phe²]GRF (1–29). This enhancement of NMDA currents was blocked by both Rp‐cAMPS and PKI_14–22 (they are highly specific PKA inhibitors), but not by the specific PKC inhibitor, bisindolylmaleimide I. In addition, the VIP‐induced enhancement of NMDA currents was accentuated by inhibition of phosphodiesterase 4, which inhibits the degradation of cAMP. This regulation of NMDA receptors also required the scaffolding protein AKAP. In contrast, the potentiation induced by high concentration of VIP (e.g., 100 nM) was mediated by PAC1‐R as well as by Src kinase. Overall, these results show that VIP can regulate NMDA receptors through different receptors and signaling pathways. © 2009 Wiley‐Liss, Inc.     

Baclofen selectively inhibits excitatory synaptic transmission in the hippocampus

The effect of baclofen was investigated on mossy fiber, Schaffer collateral and perforant path synaptic transmission in hippocampal slices. Baclofen completely inhibits mossy fiber and Schaffer collateral synaptic transmission with an IC50 of 3.8 microM. The lateral perforant path is insensitive to baclofen, while the response in the medial zone was partially blocked. Baclofen does not appear to act in a GABA-like manner.     

Influence of age on BDNF modulation of hippocampal synaptic transmission: interplay with adenosine A2A receptors

We previously reported that adenosine, through A(2A) receptor activation, potentiates synaptic actions of brain-derived neurotrophic factor (BDNF) in the hippocampus of infant (3-4 weeks) rats. Since A(2A)-receptor-mediated actions are more evident in old than in young rats and since the therapeutic potential for BDNF-based strategies is greater in old subjects, we now evaluated synaptic actions of BDNF and the levels of TrkB receptors and of adenosine A(2A) receptors in the hippocampus of three groups of adult rats: young adults (10-16 weeks), old adults (36-38 weeks), and aged (70-80 weeks), as well as in one group of infant (3-4 weeks) rats. BDNF (20 ng/ml) enhances field excitatory postsynaptic potentials recorded from the hippocampus of young adults and aged rats, an action triggered by adenosine A(2A) receptor activation, since it was blocked by the A(2A) receptor antagonist, ZM 241385. In the other groups of animals BDNF (20 ng/ml) was virtually devoid of action on synaptic transmission. Western blot analysis of receptor density shows decreased amounts of TrkB receptors in old adults and aged rats, whereas A(2A) receptor levels assayed by ligand binding are enhanced in the hippocampus of old adults and aged rats. It is concluded that age-related changes in the density of TrkB receptors and of adenosine A(2A) receptors may be responsible for a nonmonotonous variation of BDNF actions on synaptic transmission in the hippocampus.     

Cholesterol depletion inhibits synaptic transmission and synaptic plasticity in rat hippocampus

Several neurodegenerative disorders are associated with impaired cholesterol homeostasis in the nervous system where cholesterol is known to play a role in modulating synaptic activity and stabilizing membrane microdomains. In the present report, we investigated the effects of methyl-β-cyclodextrin-induced cholesterol depletion on synaptic transmission and on the expression of 1) paired-pulse facilitation (PPF); 2) paired-pulse inhibition (PPI) and 3) long-term potentiation (LTP) in the CA1 hippocampal region. Results demonstrated that cyclodextrin strongly reduced synaptic transmission and blocked the expression of LTP, but did not affect PPF and PPI. The role of glutamatergic and GABAergic receptors in these cholesterol depletion-mediated effects was evaluated pharmacologically. Data indicate that, in cholesterol depleted neurons, modulation of synaptic transmission and synaptic plasticity phenomena are sustained by AMPA-, kainate-and NMDA-receptors but not by GABA-receptors. The involvement of AMPA-and kainate-receptors was confirmed by fluorimetric analysis of intracellular calcium concentrations in hippocampal cell cultures. These data suggest that modulation of receptor activity by manipulation of membrane lipids is a possible therapeutic strategy in neurodegenerative disease.     

Topiramate alters excitatory synaptic transmission in mouse hippocampus

Antiepileptic drugs may exert neuroprotective effects by decreasing excessive membrane excitability, neurotransmitter release, or postsynaptic Ca2+ entry. To assess these sites of action, we combined fluorescence Ca2+ imaging with extracellular field recording to analyze axonal excitability, evoked presynaptic Ca2+ entry through presynaptic Ca2+ channels, postsynaptic excitatory field potentials (fEPSP), and postsynaptic Ca2+ buildup ([Capost]) at the mouse hippocampal CA3-CA1 synapse exposed to topiramate (TPM). Topiramate had no effect on presynaptic Ca2+ entry, and produced only a minor inhibition of axonal excitability. Topiramate at concentrations up to 100 microM only slightly reduced the amplitude of the evoked fEPSP, but strongly inhibited the [Capost] evoked by repetitive synaptic activation. Postsynaptically, the action of TPM on the fEPSP and [Capost] was not mediated by an inhibition of the NMDA receptor, or by direct modulation of voltage-dependent Ca2+ channels, but reflected reduced somatic or dendritic membrane depolarization by AMPA and kainate receptors. These results are consistent with the known anticonvulsant properties of TPM. In addition, the ability of TPM to reduce postsynaptic Ca2+ buildup may provide a potential mechanism for neuronal protection during paroxysmal firing associated with epileptic seizures.     

Volume-regulated anion channels do not contribute extracellular adenosine during the hypoxic depression of excitatory synaptic transmission in area CA1 of rat hippocampus

We investigated whether volume-regulated anion channels (VRACs) contributed to the accumulation of extracellular adenosine during hypoxia in area CA1. The rapid hypoxic depression of the fEPSP was greatly attenuated by the selective adenosine A1 receptor antagonist DPCPX (50 nM), but not affected by the VRAC blockers tamoxifen (10-30 microM) or DNDS (1 mM). Our data argue against the efflux of adenosine per se or its precursor ATP through VRACs as making a significant contribution to extracellular adenosine during the early stages of hypoxia.     

Functional rescue of excitatory synaptic transmission in the developing hippocampus in Fmr1-KO mouse

Pharmaceutical treatments are being developed to correct specific behavioural and morphological aspects of neurodevelopmental disorders such as mental retardation. Fragile X syndrome is an X-linked mental retardation with abnormal dendritic protrusions from neurons in the brain. Increased signalling via excitatory metabotropic glutamate receptor (mGluR) pathways is hypothesised to contribute to this disorder. Targeting these receptors has shown improvements in both behaviour and morphology with the Fmr1-KO mouse model for the syndrome. It is not known whether similar changes occur in excitatory synaptic activity following treatment with mGluR antagonists.We tested the effects of prolonged mGluR blockade on excitatory synaptic activity at three developmental time points in hippocampal slices. We observed a rescue effect of the antagonist MPEP upon spontaneous EPSC amplitude and charge at 2 weeks but not 1 week or 8–10 weeks of development. These data support the role of mGluR antagonist treatment for functional synaptic correction at an early developmental stage in a model for fragile X syndrome.     

Strontium supports synaptic transmission and long-lasting potentiation in the hippocampus

(1) Synaptic transmission was studied in isolated transverse hippocampal slices from guinea pigs. Extracellular evoked potentials were recorded in the region CA1. (2) Changing the normal perfusion solution (containing 2 mM Ca2+) to calcium-free Ringer abolished synaptic transmission which was again restored by adding strontium. A synaptic efficacy of 25--50% ofn normal was obtained for 10 mM Sr2+. (3) Two different synaptic inputs to CA1 pyramidal cells were tested with respect to their ability to produce long-lasting synaptic potentiation after tetanization in strontium Ringer. Following a brief tetanus the field EPSP and, especially, the population spike were greatly enhanced. (4) The potentiation so produced was similar to the long-lasting potentiation seen in the normal slice, because it (i) had a very long duration (hours), (ii) was specific for the tetanized pathway, (iii) showed potentiation of both 'volley-EPSP' and 'EPSP-spike' relations, and (iv) was accompanied by short-lasting (less than 5 min) generalized depression.     

Chronic liver failure in rats impairs glutamatergic synaptic transmission and long-term potentiation in hippocampus and learning ability

Cognitive function is impaired in patients with liver disease by unknown mechanisms. Long-term potentiation (LTP) in the hippocampus is considered the basis of some forms of learning and memory. The aims of this work were to assess (i) whether chronic liver failure impairs hippocampal LTP; (ii) if this impairment may be due to alterations in glutamatergic neurotransmission, and (iii) if impairment of LTP is associated with reduced learning ability. It is shown that liver failure in Wistar rats induces the following alterations in the hippocampus; (i) alters the phosphorylation of NMDA and AMPA receptors; (ii) reduces the expression of NMDA and AMPA receptors in membranes, (iii) reduces the magnitude of excitatory postsynaptic potentials (EPSPs) induced by activation of NMDA or AMPA receptors, and (iv) impairs NMDA receptor-dependent LTP. Liver failure also impairs learning of the Morris water maze task. Impairment of glutamatergic synaptic transmission and NMDA receptor-mediated responses may be involved in the alterations of cognitive function in patients with liver disease.     

Evidence for the functional role of monosialoganglioside GM1 in synaptic transmission in the rat hippocampus

The hippocampal slices were incubated with compounds which hydrolyze, modify or bind with sialic acid containing molecules. The efficiency of synaptic transmission was tested in the presence of these compounds. The size of the evoked extracellularly recorded potential following Schaffer collateral stimulation was used as an indicator of synaptic transmission efficiency. Sodium periodate (10 mM) and sodium perchlorate (59.2 mM) evoked a reversible (after washout) decrease in the size of the population spike. Higher concentration of sodium periodate (60 mM) abolished the size of the population spike, which was only poorly reversible after washout. Tetanus toxin, which binds to polysialogangliosides, and neuraminidase from Vibrio cholerae (an enzyme which splits off sialic acid from polysialogangliosides, leaving GM1 intact, and splits off sialic acid from sialoglycoproteins) had no influence on the size of the population spike. Cholera toxin, which binds to GM1, slightly reduced the size of the population spike. Incubation of the slices with neuraminidase from Arthrobacter ureafaciens (an enzyme which splits off sialic acid from all gangliosides, including GM1, and from sialoglycoproteins) abolished the population spike after 5 h. GM1 antiserum abolished the potential after approximately 100 min. The conclusion is drawn that of all gangliosides only GM1 is necessary to support synaptic transmission in Schaffer collateral-pyramidal cell synapses.     

Actions of somatostatin on GABA-ergic synaptic transmission in the CA1 area of the hippocampus.

Somatostatin and gamma-aminobutyric acid (GABA) are co-localized in some neurons in the CA1 area of the hippocampus. Since it is possible that the peptide and the amino acid are co-released, the interactions between the actions of somatostatin and GABA-ergic inhibitory post-synaptic potentials (IPSPs) in the CA1 pyramidal neurons of guinea pig hippocampal slices have been investigated. Somatostatin (2 microM) induced a hyperpolarization of the CA1 neurons associated with a reduction in the input resistance of the cells. These effects were not blocked by picrotoxinin (20 microM) or phaclofen (1 mM). Chelation of intracellular Ca2+ (Ca2+i) with BAPTA or the inhibition of protein kinase C (PKC) with sphingosine (30 microM) had no significant effects on the hyperpolarizing actions of somatostatin. The peptide suppressed the GABAA receptor-mediated fast IPSPs and the GABAB receptor-mediated slow IPSPs, but had no significant effect on the excitatory post-synaptic potentials (EPSPs). Somatostatin-induced depression of the IPSPs was not due to the hyperpolarization of the neurons. Baclofen (20 microM) suppressed the EPSP, as well as the fast and the slow IPSPs. The hyperpolarization of the CA1 neurons caused by somatostatin was greatly reduced in the presence of baclofen, an effect that was not due to the hyperpolarization of the cell by baclofen. The presence of QX-314 in the CA1 neurons, which suppressed the Na+ spikes and the slow IPSPs, prevented the hyperpolarization of the neurons by somatostatin and baclofen.(ABSTRACT TRUNCATED AT 250 WORDS)