Synaptic Transmission In Dentate Gyrus Research Articles

The complement inhibitor CD59 is required for GABAergic synaptic transmission in the dentate gyrus

Complement-dependent microglia pruning of excitatory synapses has been widely reported in physiological and pathological conditions, with few reports concerning pruning of inhibitory synapses or direct regulation of synaptic transmission by complement components. Here, we report that loss of CD59, an important endogenous inhibitor of the complement system, leads to compromised spatial memory performance. Furthermore, CD59 deficiency impairs GABAergic synaptic transmission in the hippocampal dentate gyrus (DG). This depends on regulation of GABA release triggered by Ca2+ influx through voltage-gated calcium channels (VGCCs) rather than inhibitory synaptic pruning by microglia. Notably, CD59 colocalizes with inhibitory pre-synaptic terminals and regulates SNARE complex assembly. Together, these results demonstrate that the complement regulator CD59 plays an important role in normal hippocampal function.

Hippocampal astrocytes modulate anxiety-like behavior

Astrocytes can affect animal behavior by regulating tripartite synaptic transmission, yet their influence on affective behavior remains largely unclear. Here we showed that hippocampal astrocyte calcium activity reflects mouse affective state during virtual elevated plus maze test using two-photon calcium imaging in vivo. Furthermore, optogenetic hippocampal astrocyte activation elevating intracellular calcium induced anxiolytic behaviors in astrocyte-specific channelrhodopsin 2 (ChR2) transgenic mice (hGFAP-ChR2 mice). As underlying mechanisms, we found ATP released from the activated hippocampal astrocytes increased excitatory synaptic transmission in dentate gyrus (DG) granule cells, which exerted anxiolytic effects. Our data uncover a role of hippocampal astrocytes in modulating mice anxiety-like behaviors by regulating ATP-mediated synaptic homeostasis in hippocampal DG granule cells. Thus, manipulating hippocampal astrocytes activity can be a therapeutic strategy to treat anxiety.

Brain-Derived Neurotrophic Factor Potentiates Entorhinal-Dentate but not Hippocampus CA1 Pathway in Adult Male Rats: A Mechanism of Taurine-Modulated BDNF on Learning and Memory.

Taurine plays an important role in neural growth and function from early to adult life, particularly in learning and memory via BDNF action. This study tested the hypothesis that BDNF differentially potentiates entorhinal-hippocampal synaptic transmission in vivo in adult rats. In anesthetized male Sprague-Dawley rats, a stainless steel recording electrode with an attached microinjector was placed into CA1 and the dentate gyrus to record fEPSP, and a paired stainless steel electrode was inserted into entorhinal cortex for continuous paired-pulse stimulation of that brain region. In the dentate gyrus, microinjection of BDNF resulted in a gradual increase in the peak slope of the fEPSP. Following the infusion, the peak fEPSP began to rise in about 8min, reached a maximum of 120±2% (from baseline) by about 20min, and remained near peak elevation (~115%) for more than 30 min. In contrast, the same dose of BDNF when injected into CA1 had no consistent effect on fEPSP slopes in the CA1. Further, an equimolar cytochrome C (horse heart) infusion had no significant effect on fEPSP slopes in either the dentate gyrus or CA1. The potentiation effect of BDNF in the dentate gyrus is consistent with a significant increase in power spectral density of dentate gyrus field potentials at 70-200Hz, but not at frequencies below 70 Hz. In addition, the CA1 power spectral density was not affected by BDNF (compared to cytochrome C). These data indicate that in vivo BDNF potentiates entorhinal-hippocampal synaptic transmission in dentate gyrus, but not in CA1.

Reward memory relieves anxiety-related behavior through synaptic strengthening and protein kinase C in dentate gyrus.

Anxiety disorders are presumably associated with negative memory. Psychological therapies are widely used to treat this mental deficit in human beings based on the view that positive memory competes with negative memory and relieves anxiety status. Cellular and molecular processes underlying psychological therapies remain elusive. Therefore, we have investigated its mechanisms based on a mouse model in which food reward at one open-arm of the elevated plus-maze was used for training mice to form reward memory and challenge the open arms. Mice with the reward training showed increased entries and stay time in reward open-arm versus neutral open-arm as well as in open-arms versus closed-arms. Accompanying with reward memory formation and anxiety relief, glutamatergic synaptic transmission in dentate gyrus in vivo and dendritic spines in granule cells became upregulated. This synaptic up-regulation was accompanied by the expression of more protein kinase C (PKC) in the dendritic spines. The inhibition of PKC by chelerythrine impaired the formation of reward memory, the relief of anxiety-related behavior and the up-regulation of glutamate synapses. Our results suggest that reward-induced positive memory relieves mouse anxiety-related behavior by strengthening synaptic efficacy and PKC in the hippocampus, which imply the underlying cellular and molecular processes involved in the beneficial effects of psychological therapies treating anxiety disorders.

Inhibition of long‐term potentiation by CuZn superoxide dismutase injection in rat dentate gyrus: Involvement of muscarinic M1 receptor

Long-term potentiation (LTP) and long-term depression represent important processes that modulate synaptic transmission that carries out a key role in neural mechanisms of memory. Many studies give strong evidences on a role of the reactive oxygen species in the induction of LTP in CA1 region of hippocampal slices that was inhibited by adding the scavenger enzyme superoxide dismutase (SOD1). Previous data showed that SOD1 is secreted by many cellular lines, including neuroblastoma SK-N-BE cells through microvesicles by an ATP-dependent mechanism; moreover, it has been shown that SOD1 interacts with human neuroblastoma cell membranes increasing intracellular calcium levels via a phospholipase C-protein kinase C pathway activation. The aim of this study was to investigate the effect of intracerebral injection of SOD1 or the inactive form of enzyme (ApoSOD) on the modulation of synaptic transmission in dentate gyrus of the hippocampus in urethane anesthetized rats. The results of the present research showed that intracerebral injection of SOD1 and ApoSOD in the dentate gyrus of the rat hippocampal formation inhibits LTP induced by high-frequency stimulation of the perforant path. This result cannot be only explained by the dismutation of oxygen radical induced by SOD1 since also ApoSOD, that lacks the enzymatic activity, carries out the same inhibitory effect on LTP induction.

Effect of low frequency stimulation of perforant path on kindling rate and synaptic transmission in the dentate gyrus during kindling acquisition in rats

Low frequency stimulation (LFS) has an inhibitory effect on kindling acquisition. In the present study the effect of the perforant path LFS on induction of rapid perforant path kindled seizures and synaptic transmission in the dentate gyrus was investigated. Animals were kindled by perforant path stimulation in a rapid kindling manner (12 stimulations per day). In one group of animals LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, and 50-150 microA) was applied to perforant path, immediately after termination of each rapid kindling stimulation. Application of LFS significantly retarded the kindling acquisition and increased the number of stimulations to achieved different kindled seizure stages. LFS also prevented an increment in the slope of field excitatory postsynaptic potentials and population spike amplitude during kindling. In addition, LFS significantly reduced the marked increase in early (10-50 ms intervals) and late (300-1000 ms intervals) paired-pulse depression induced by kindling. According to obtained results, it may be suggested that LFS of perforant path has a significant antiepileptogenic effect through inhibition of synaptic transmission in dentate gyrus. Meanwhile, LFS prevents an increase in the paired-pulse depression during kindling acquisition.

Effect of corticosteroid treatment in vitro on adrenalectomy-induced impairment of synaptic transmission in the rat dentate gyrus.

Removal of the rat adrenals results after 3 days in the appearance of apoptotic cells in the dentate gyrus. Apoptosis is accompanied by an impaired synaptic transmission in the dentate gyrus. Substitution in vivo with a low dose of corticosterone was found to prevent both the appearance of apoptotic cells and the functional impairment. In the present study we determined whether the functional normalisation after corticosterone treatment critically depends on prevention of apoptosis. To address this question, brain slices from rats showing apoptosis after adrenalectomy were treated in vitro with the mineralocorticoid aldosterone (3 nM) or with 30 nM corticosterone, which is assumed to activate both mineralo- and glucocorticoid receptors. Steroids were briefly applied either during recording (acute effects) or several hours before recording (long-term effects). While the slope of the fEPSP recorded in the outer molecular layer of the dentate gyrus in response to perforant path stimulation was not affected up to 1 h after acute administration of the steroids, fEPSP slopes recorded 2.5-3 h after corticosterone or aldosterone treatment were significantly increased, to the level of the sham-operated controls. The results indicate that delayed corticosteroid effects through in vitro activation of mineralocorticoid receptors (MRs) are sufficient to normalise synaptic transmission in the dentate gyrus of ADX rats, even in the presence of apoptotic cells. We tentatively conclude that the impaired synaptic transmission seen after ADX is probably not primarily caused by the appearance of apoptotic cells.

On the mechanism of histaminergic inhibition of glutamate release in the rat dentate gyrus.

1. Histaminergic depression of excitatory synaptic transmission in the rat dentate gyrus was investigated using extracellular and whole-cell patch-clamp recording techniques in vitro. 2. Application of histamine (10 microM, 5 min) depressed synaptic transmission in the dentate gyrus for 1 h. This depression was blocked by the selective antagonist of histamine H3 receptors, thioperamide (10 microM). 3. The magnitude of the depression caused by histamine was inversely related to the extracellular Ca2+ concentration. Application of the N-type calcium channel blocker omega-conotoxin (0. 5 or 1 microM) or the P/Q-type calcium channel blocker omega-agatoxin (800 nM) did not prevent depression of synaptic transmission by histamine. 4. The potassium channel blocker 4-aminopyridine (4-AP, 100 microM) enhanced synaptic transmission and reduced the depressant effect of histamine (10 microM). 4-AP reduced the effect of histamine more in 2 mM extracellular calcium than in 4 mM extracellular calcium. 5. Histamine (10 microM) did not affect the amplitude of miniature excitatory postsynaptic currents (mEPSCs) and had only a small effect on their frequency. 6. Histaminergic depression was not blocked by an inhibitor of serine/threonine protein kinases, H7 (100 microM), or by an inhibitor of tyrosine kinases, Lavendustin A (10 microM). 7. Application of adenosine (20 microM) or the adenosine A1 agonist N6-cyclopentyladenosine (CPA, 0.3 microM) completely occluded the effect of histamine (10 microM). 8. We conclude that histamine, acting on histamine H3 receptors, inhibits glutamate release by inhibiting presynaptic calcium entry, via a direct G-protein-mediated inhibition of multiple calcium channels. Histamine H3 receptors and adenosine A1 receptors act upon a common final effector to cause presynaptic inhibition.

Synaptic transmission in the rat dentate gyrus after adrenalectomy

Granule cells in the rat hippocampal dentate gyrus contain intracellular receptors for the adrenal hormone corticosterone. Activation of these receptors seems essential for granule cell viability, since removal of the adrenal gland (adrenalectomy) results within three days in apoptotic-like degeneration of granule cells. In the present study we used extracellular in vitro recording methods to study the synaptic transmission in the dentate gyrus of adrenalectomized animals, in sham-operated controls and adrenalectomized rats treated with a low dose of corticosterone. We found that particularly three days after adrenalectomy orthodromic field responses in the dentate gyrus were reduced in amplitude. Corticosterone-treated rats did not show this impairment of synaptic transmission. Antidromically-evoked field responses were also reduced after adrenalectomy, which indicates that postsynaptic cell properties rather than signal transduction in the synapses are under steroid control. Responses to paired pulse stimulation were only marginally affected, suggesting that interneuronal networks may be less affected by the hormones than the principal cells. These electrophysiological data indicate that adrenalectomy induced apoptotic-like degeneration in the hippocampal dentate gyrus is clearly associated with impaired processing of incoming information.

Early impairment and late recovery of synaptic transmission in the rat dentate gyrus following transient forebrain ischemia in vivo

Ischemic stroke causes various functional deficits in the brain such as memory impairment, and clinical reports have shown that the impaired brain functions may partially recover. However, there has been no experimental model suitable for studying cellular mechanisms of functional recovery following brain ischemia. Therefore, we investigated the long-term influence of transient forebrain ischemia on excitatory synaptic transmission in the rat dentate gyrus, a brain region relatively resistant to ischemia. Fifteen minutes of transient forebrain ischemia produced no apparent histological damage in dentate granule cells, but caused a significant reduction of basal synaptic potentials evoked by perforant path stimulation. Field excitatory postsynaptic potential remained reduced for at least 1 month after ischemia, while population spike recovered to control level in 1 month. The induction of long-term potentiation was also impaired after ischemia, but it showed faster recovery than basal synaptic potentials. In conclusion, we found that synaptic transmission in the dentate gyrus of the rat is impaired following transient forebrain ischemia, but has a potential to recover. These results may provide a good model for studying the mechanisms of impairment and recovery of brain function after transient ischemia.

Acute intrahippocampal infusion of BDNF induces lasting potentiation of synaptic transmission in the rat dentate gyrus.

The effect of acute intrahippocampal infusion of brain-derived neurotrophic factor (BDNF) on synaptic transmission in the dentate gyrus was investigated in urethan-anesthetized rats. Medial perforant path-evoked field potentials were recorded in the dentate hilus and BDNF-containing buffer was infused (4 microl, 25 min) immediately above the dentate molecular layer. BDNF led to a slowly developing increase of the field excitatory postsynaptic potential (fEPSP) slope and population spike amplitude. The potentiation either reached a plateau level at approximately 2 h after BDNF infusion or continued to increase for the duration of experiment; the longest time point recorded was 10 h. Mean increases at 4 h after BDNF infusion were 62.2 and 224% for the fEPSP slope and population spike, respectively. No changes in responses were observed in controls receiving buffer medium only or buffer containing cytochrome C. BDNF-induced potentiation developed in the absence of epileptiform activity in the hippocampal electroencephalogram or changes in recurrent inhibition on granule cells as assessed by paired-pulse inhibition of the population spike. We conclude that exogenous BDNF induces a lasting potentiation of synaptic efficacy in the dentate gyrus of anesthetized adult rats.

Gangliosides improve synaptic transmission in dentate gyrus of hippocampal rat slices

The effect of perfusion with gangliosides (1 × 10 −6M) on the response evoked in the granule cell layer of dentate gyrus by stimulation of perforant path in hippocampal rat slices was studied. Gangliosides induced both a decrease in the frequency threshold of stimulation necessary to generate long-term potentiation (LTP) and greater potentiation than under control conditions. It is proposed that gangliosides improve the mechanisms responsible for synaptic plasticity which generate LTP.

Altered synaptic transmission in dentate gyrus of rats reared in complex environments: evidence from hippocampal slices maintained in vitro.

Pre- and postsynaptic responses to activation of medial perforant path (MPP) axons were examined in hippocampal slices taken from rats reared for 3-4 wk in relatively complex (EC) or individual cage (IC) environments. Three types of extracellular field potentials were recorded in the infrapyramidal blade of the dentate gyrus: 1) granule cell population spikes (PSs), which reflect the number and synchrony of discharging granule cells (2), 2) population excitatory postsynaptic potentials (EPSPs), which reflect the amount of excitatory synaptic current flow into dendrites (28), and 3) presynaptic fiber volleys (FVs), which reflect the number of activated axons (28). Stimulation of the MPP evoked significantly larger PSs in slices taken from EC rats. There was no significant effect of rearing environment on PS/EPSP relationships. The slopes of EPSPs recorded at the site of synaptic activation in the dentate molecular layer and at the major current source in the dentate granule cell layer were significantly greater in slices taken from EC rats. The presynaptic FV was recorded at the site of synaptic activation in the molecular layer. FV amplitude did not differ significantly as a function of rearing environment. To examine possible differences in tissue impedance, granule cells were activated by stimulating granule cell axons in the dentate hilus and recording the antidromic PS in the granule cell layer. Antidromic PS amplitude was not significantly affected by rearing environment. The relative permanence of the experience-dependent alterations in synaptic transmission was assessed by comparing slices taken from rats that had been reared for 4 wk in complex environments followed by 3-4 wk in individual cages with those from rats reared for 7-8 wk in individual cages. There were no significant differences in MPP synaptic transmission between these groups of animals. The results suggest that experience in a relatively complex environment is associated with greater MPP synaptic transmission arising from an increased synaptic input to granule cells; the greater MPP synaptic transmission associated with behavioral experience can occur independent of behavioral state, influences from extrahippocampal brain regions and intrahippocampal inhibitory activity; and the experience-dependent synaptic alterations in the dentate gyrus are transient, in contrast to experience-dependent morphological alterations described in occipital cortex. The possible relationship of these alterations to the phenomenon of long-term enhancement is discussed.