Dentate Gyrus Of Urethane-anesthetized Rats Research Articles

Vagus nerve stimulation induced long-lasting enhancement of synaptic transmission and decreased granule cell discharge in the hippocampal dentate gyrus of urethane-anesthetized rats

Vagus nerve stimulation (VNS) ameliorates deficits of hippocampal functions, such as contextual learning and memory, probably through direct modulation of neuronal activity. Previous studies showed that VNS enhanced excitatory synaptic transmission in the hippocampal CA3 area via activation of β-adrenergic receptors. However, effects of VNS on excitatory synaptic transmission and action potential (AP) discharge of granule cells (GCs) in the dentate gyrus have not been studied. Urethane-anesthetized rats were used to investigate whether VNS influences synaptic transmission efficacy at perforant path-GC synapses and population spike discharge in the dentate gyrus. Intermittent burst stimulation of the left vagus nerve (30Hz for 30s at an inter-train interval of 5min for 1h) significantly enhanced the perforant path-GC synaptic transmission efficacy in the dentate gyrus for at least 2h, indicating that VNS can induce a long-lasting enhancement of synaptic transmission in this area, similar to the situation observed in the CA3 area. In contrast, a 60-min period of VNS significantly reduced population spike amplitude (a parameter reflecting synchronized AP discharge of GCs) for a given excitatory postsynaptic potential. These findings suggest that acute VNS enhances the excitatory synaptic transmission and reduces synchronized AP discharge of GCs in the dentate gyrus. It is likely that enhancement of excitatory synaptic transmission and reduction of GC excitability contribute VNS treatment efficacy for learning deficits and intractable epilepsy, respectively.

“Heterosynaptic” LTD in the Dentate Gyrus of Anesthetized Rat Requires Homosynaptic Activity

Heterosynaptic long-term depression (LTD) is conventionally defined as occurring at synapses that are inactive during a time when neighboring synapses are activated by high-frequency stimulation. A new model that combines computational properties of both the Bienenstock, Cooper and Munro model and spike timing-dependent plasticity, however, suggests that such LTD actually may require presynaptic activity in the depressed pathway. We tested experimentally whether presynaptic activity is in fact necessary for previously described heterosynaptic LTD in lateral perforant path synapses in the dentate gyrus of urethane-anesthetized rats. As predicted by the model, procaine infusion into the lateral path fibers, sufficient to transiently block neural activity in this pathway, prevented the induction of LTD in the lateral path following medial path high-frequency stimulation. These data indicate that the previously described heterosynaptic LTD in the dentate gyrus in vivo is actually a form of homosynaptic LTD, requiring presynaptic activity in the depressed pathway.

Locus Ceruleus Activation Suppresses Feedforward Interneurons and Reduces β-γ Electroencephalogram Frequencies While It Enhances θ Frequencies in Rat Dentate Gyrus

The locus ceruleus is activated by novel stimuli, and its activation promotes learning and memory. Phasic activation of locus ceruleus neurons by glutamate enhances the dentate gyrus population spike amplitude and results in long-term potentiation of synaptic responses recorded after 24 h. Cholinergic activation of locus ceruleus neurons increases hippocampal . At the level of the cellular network, it is not clear how the potentiating effects of norepinephrine are mediated. Previous studies show that exogenous norepinephrine enhances inhibitory interneuron firing in the dentate gyrus. This finding appears at odds with evidence for potentiation. In this study, natural release of norepinephrine was induced by glutamate activation of locus ceruleus while we recorded EEGs and physiologically identified interneurons in the dentate gyrus of urethane-anesthetized rats. Feedforward neurons were inhibited (approximately 1-2 min) by locus ceruleus activation. Feedback interneurons showed both increased and decreased activity, whereas granule cells increased firing as predicted by evoked potential studies. EEG results replicated an increase in power (4-8 Hz) with locus ceruleus activation, but the effect with glutamatergic locus ceruleus activation was transient (approximately 1-2 min). Beta-gamma Frequencies were also transiently suppressed. Together, the data suggest that locus ceruleus activation enhances the throughput of concomitant sensory input by reducing feedforward inhibitory interneuron activity, which may reduce "binding" in existing cell assemblies, and enhances the conditions for synaptic plasticity through disinhibition, promotion of 4-8 Hz , and noradrenergic potentiation to facilitate the building of new representations.

Effects of reversible inactivation of the medial septal area on long-term potentiation and recurrent inhibition of hippocampal population spikes in rats

We assessed the effects of reversible inactivation of the medial septal area (MSA) on long-term potentiation (LTP) and recurrent inhibition in the dentate gyrus of urethane-anesthetized rats, in vivo. The septal input to the hippocampus was temporarily eliminated by injection of tetrodotoxin (TTX, 10 ng/1 μl) into the MSA. In Experiment 1, LTP inducibility was examined in the perforant-dentate gyrus synapses in the MSA inactivated and control rats by 2 high-frequency stimulation (HFS), 5 min apart, applied to the perforant pathway (PP). The magnitude of potentiation was evaluated as the percentage change in the population spike (PS) amplitude at 5, 30, 60 or 120 min after the second HFS. The PS amplitude in the MSA inactivated rats was significantly lower than those of control group at 120 but not 5, 30 or 60 min after the second HFS. The MSA inactivation itself had no effect on the basal responses evoked by test stimuli. In Experiment 2, the MSA inactivation did not affect the efficacy of recurrent inhibition in the perforant-dentate gyrus synapses produced by paired pulses applied to the PP at 10- and 20-ms interpulse intervals. These results indicate that: (1) although hippocampal synapses can be still potentiated after the HFS in the MSA inactivated animals, a faster decay of LTP may be due to elimination of the MSA output amplification on synaptic responses mediated by excitatory amino acids; and (2) the recurrent inhibition mechanism in the dentate gyrus of the hippocampus is not probably affected by the MSA inactivation.

Increase in activin βA mRNA in rat hippocampus during long-term potentiation

We have used mRNA differential display to isolate genes that are induced by neural activity in rat hippocampus. One of these encodes activin βA subunit. Convulsive seizure caused by kainate significantly induced the expression of activin βA mRNA. Furthermore high frequency stimulation (HFS) of perforant pathway, which produced a persistent long-term potentiation (LTP) (> 10 h), caused a marked increase at 3 h in the level of activin βA mRNA at the dentate gyrus of urethane-anesthetized rat. The increase was NMDA receptor-dependent. By contrast the level of inhibin α mRNA was not changed following the induction of LTP. The results suggest a role for activin in maintenance of neural plasticity in the adult brain.

GABA B receptors modulate synaptically-evoked responses in the rat dentate gyrus, in vivo

We assessed the effects of systemically injected baclofen, a GABA B agonist, on single and paired-pulse responses in the dentate gyrus of urethane-anesthetized rats, in vivo. Baclofen (10 mg/kg) significantly increased the duration of single excitatory responses. This increase was blocked by the GABA B receptor antagonist, CGP 35348, indicating that baclofen was acting through GABA B receptors. To determine the mechanism underlying this increase in response duration, the NMDA antagonist, d-2-amino-5-phosphonopentanoic acid ( d-APV), was administered intracerebroventricularly (i.c.v.) after baclofen. d-APV by itself had no effect on the duration of the population excitatory post-synaptic potential (EPSP). However, when infused after baclofen, d-APV blocked the baclofen induced increase in EPSP duration. This indicates the prolonged EPSP duration caused by baclofen resulted from an enhancement of an NMDA receptor mediated component of the response. We then examined the effect of baclofen on population responses to paired stimuli. Baclofen attenuated paired-pulse inhibition of population spike amplitudes at a 25 ms interstimulus interval. CGP-35348 reduced the effect of baclofen on paired-pulse inhibition, indicating that baclofen suppressed paired-pulse inhibition by acting on GABA B receptors. In contrast to its disinhibitory effect at the 25 ms interval, baclofen had an inhibitory effect on responses evoked at a 150 ms interstimulus interval. Under control conditions, we observed that when stimuli were delivered 150 ms apart, both the EPSP duration and population spike amplitude evoked by the second stimulus were enhanced. Baclofen suppressed this enhancement. We conclude that GABA B receptor activation by baclofen reduces short interval inhibition and this reduction of inhibition leads to an enhanced NMDA-receptor mediated response. We also conclude that by reducing inhibition, baclofen occludes paired-pulse disinhibition found at longer interstimulus intervals. In contrast, CGP-35348 directly blocks paired-pulse disinhibition. Thus, GABA B receptor activation can regulate synaptic inhibition, in turn influencing NMDA receptor activation and synaptic transmission. Thus, pharmacologic manipulation of GABA B receptors may provide a powerful approach for regulating synaptic transmission in the hippocampus.

The [formula omitted] channel blocker ketamine does not attenuate, but enhances, locus coeruleus-induced potentiation in rat dentate gyrus

Norepinephrine (NE)-induced potentiation of the perforant path-evoked poten3ial is blocked by N- methyl- d-aspartate (NMDA) receptor antagonism in vitro. Does this occur in vivo? A saline and a ketamine micropipette monitored perforant path-evoked potentials in the dentate gyrus of urethane-anesthetized rats. Activation of locus coeruleus (LC) produced short- and long-term potentiation of the perforant path-evoked potential on both pipettes. Spike amplitude potentiation was enhanced on the ketamine pipette. In contrast high frequency-induced potentiation on the ketamine pipette was attenuated. LC-NE potentiation may not require NMDA channel activation in vivo.

NMDA receptors have a dominant role in population spike-paired pulse facilitation in the dentate gyrus of urethane-anesthetized rats

Paired-pulse facilitation was studied at the perforant path-granule cell synapses in the dentate gyrus of urethane-anesthetized rats. Extracellular field potentials comprising excitatory postsynaptic potentials (EPSPs) and population spikes (PSs) were used to compare facilitation of both responses at interpulse intervals between 10 and 1000 ms. In this model system EPSPs, produced at stimulus intensities well below the PS threshold, exhibited paired-pulse facilitation (PPF) at intervals less than 40 ms. Between 40 and 100 ms both responses were of equal size and from 200 to 1000 ms the second response exhibited paired-pulse depression (PPD). With higher stimulus intensities, PSs exhibited early (10–30 ms) and late (400–1000 ms) PPD and intermediate interval (40–200 ms) PPF. The enhanced PS amplitude during facilitation was accompanied by a modest decrease in EPSP slope and increase in PS latencies to onset and to peak. If PS amplitude was increased to the same extent by simply increasing stimulus intensity, an increase in EPSP slope and decrease in PS latencies to onset and peak were observed. Current source-density analysis revealed that the current sink generated by synaptic activation of granule cell dendrites was indistinguishable between control and facilitated responses up to the onset of the PS. However, the facilitated response exhibited a marked increase in the duration and amplitude of current flowing into the dendrites during the late phase of the EPSP. PPF of the PS was attenuated or blocked by the administration of the known NMDA receptor-ion channel blockers, MK-801, dextromethorphan and ketamine. The depressant effects of these pharmacological agents on facilitation shared the same time course as facilitation itself, peaking at 60 ms and lasting approximately 200 ms. These data suggest that facilitation in this situation is due to postsynaptic rather than presynaptic modulations, and is based upon an increase in the NMDA-mediated component of the evoked response. No increase in transmitter release, per se, could be demonstrated.

NMDA receptor antagonists block the induction of long-term depression in the hippocampal dentate gyrus of the anesthetized rat

The present study tested the effect of two non-competitive NMDA receptor antagonists, ketamine and phencyclidine, on the induction of long-term depression (LTD) in the dentate gyrus of urethane-anesthetized rats. Both drugs blocked the induction of LTD as well as long-term potentiation (LTP). NMDA receptor activation thus seems to be required for the induction of both LTD and LTP in the dentate gyrus. High-intensity conditioning stimulation did not overcome the phencyclidine block of LTD. Strong, but brief, postsynaptic depolarization is apparently not the only event needed to trigger LTD.

A newly discovered protein kinase C activator (oleic acid) enhances long-term potentiation in the intact hippocampus

Protein kinase C can be activated by oleate, an unsaturated fatty acid. Since protein kinase C is activated by long-term potentiation, we wished to determine whether iontophoretic ejection of oleate into the intact hippocampal dentate gyrus of urethane-anesthetized rats would cause an enhancement of the response potentiated by high frequency stimulation of the perforant path. Oleate ejection did significantly enhance the persistence of the potentiated response. Moreover, a growth of the response beyond the initial potentiation was seen. Arachidonate, which stimulates protein kinase C to a lesser degree, had a significant preservation effect, but no effect on growth of the response. After vehicle and elaidate (trans-stereoisomer of oleate) ejections, the potentiated response decayed to baseline values. In addition, the persistence of the potentiated response observed two hours after its induction was positively correlated with the ability of an unsaturated fatty acid to activate protein kinase C in vitro. The present results support the proposal that protein kinase C activation enhances synaptic strength. It is suggested that one mechanism for this activation may be PLA2-mediated release of oleate.