Perforant Path-evoked Population Spike Research Articles

Modulation of the perforant path‐evoked potential in dentate gyrus as a function of intrahippocampal β‐adrenoceptor agonist concentration in urethane‐anesthetized rat

Backgroundβ-adrenoceptor activation in the hippocampus is sufficient to induce heterosynaptic long-term potentiation of perforant path input to the dentate gyrus. However, in vitro and in vivo studies suggest the plasticity effects of β-adrenoceptor activation may vary depending on the level of receptor activation.MethodsThe present experiments use an in vivo model concurrently infusing differing concentrations of the β-adrenoceptor agonist, isoproterenol (ISO; 0, 0.1, 1, 10, and 100 μmol/L in aCSF; 1 μL over 12.5 min) in the dentate gyrus, while monitoring changes in the perforant path-evoked potential at the same site.ResultsLong-term depression (LTD) of fEPSP slope was elicited by 0.1 μmol/L ISO. Higher doses did not alter fEPSP slope. Maximal long-term potentiation of the perforant path-evoked population spike (183% >3 h) occurred at 10 μmol/L ISO. Transient depression of spike amplitude occurred at 0.1 μmol/L ISO.ConclusionsThese data demonstrate concentration-dependent effects of β-adrenoceptor activation on the perforant path-evoked potential. Long-term depression and long-term potentiation of perforant path-evoked responses are variably elicited as a function of the degree of receptor activation.

Idazoxan increases perforant path-evoked EPSP slope paired pulse inhibition and reduces perforant path-evoked population spike paired pulse facilitation in rat dentate gyrus

Norepinephrine, acting via β-adrenoceptors, enhances the perforant path-evoked potential in dentate gyrus. Using systemic idazoxan to increase norepinephrine, and paired perforant path pulses to probe early inhibition, previous investigators reported that idazoxan increased initial spike amplitude and increased somatic feedback inhibition. Here, feedback inhibition was re-examined in idazoxan-treated (5 mg/kg) rats under urethane anesthesia. To control for initial increased spike amplitude after idazoxan, evoked potentials were matched, pre- and post-idazoxan, on initial population spike. Input–output current profiles were also compared pre- and post-idazoxan. Saline- and timolol-filled micropipettes permitted evaluation of a contribution of local β-adrenoceptors. As previously observed, initial spike amplitude was potentiated by idazoxan. Comparable spike potentiation was not seen on the timolol micropipette. Paired pulse inhibition of spike amplitude apparently increased, but input–output curve comparisons revealed a loss of feedback facilitation rather than an increase in feedback inhibition. Initial EPSP slopes were depressed after idazoxan in input–output curve data. EPSP slope feedback ratios were significantly reduced following idazoxan.These data suggest idazoxan has multiple effects on perforant path input to the dentate gyrus. Spike potentiation following idazoxan has previously been shown to depend on intact norepinephrine input. Here, the reduction in spike potentiation on the timolol pipette is consistent with other evidence that norepinephrine-mediated potentiation of the perforant path-evoked potential is dependent on local β-adrenoceptor activation. The input–output data suggest a decrease in feedback facilitation after idazoxan is likely to account for the apparent increase in feedback inhibition previously reported. Decreased EPSP slope ratios with similar paired pulse intervals have been reported in novel environments. Since exposure to novel environments activates locus coeruleus neurons, norepinephrine may mediate the change in EPSP slope inhibition reported in awake rats.In summary, these results are consistent with the hypothesis that idazoxan potentiates granule cell responses to perforant path input in the dentate gyrus via increases in norepinephrine that lead to β-adrenoceptor activation, and, further, that idazoxan reduces paired pulse feedback spike facilitation and enhances EPSP slope, but not spike, feedback inhibition.

Estimating the synaptic concentration of norepinephrine in dentate gyrus which produces β-receptor mediated long-lasting potentiation in vivo using microdialysis and intracerebroventricular norepinephrine

Norepinephrine in the hippocampus of urethane anesthetized rats was monitored by microdialysis prior to, and following, an intracerebroventricular injection of 5 μg [−]NE in 2 μl of ACSF. The perforant path evoked potential in dentate gyrus was concurrently monitored by a microelectrode adjacent to the dialysis probe. NE levels 30 X basal values or greater at the recording site were related to long-lasting potentiation of the perforant path-evoked population spike. Increases of 3 X to 6 X basal NE values were not accompanied by any potentiation. NE in the midline ventricles alone did not produce potentiation. These results suggest effective NE concentrations for β-receptor activation of long-term potentiation would only occur near the NE release site.

Non-reactivating effects of HI-6 on hippocampal neurotransmission.

Effects of the oxime HI-6, unrelated to reactivation of acetylcholinesterase (AChE), on field potentials in the dentate gyrus of the rat hippocampus following AChE inhibition, were investigated both in vitro and in vivo. In hippocampal slices, AChE inhibition decreased the perforant path evoked population spike amplitude (PSA). This effect could be prevented by pre-incubation of the slices with atropine (0.1-1 microM) or with the M1 muscarinic receptor antagonist pirenzepine (1 microM). A similar preventive effect was found after pre-incubation with the GABAA antagonist picrotoxin (20 microM), suggesting that the effects of AChE inhibition in vitro may be due to an enhancement of GABAergic inhibitory activity via activation of M1-muscarinic receptors. The effects of AChE inhibition in vivo were variable; both increases and decreases of the PSA were found. Following AChE inhibition, HI-6 increased the PSA dose-dependently, both in the in vivo and in the in vitro hippocampus. At higher oxime doses the perforant path stimulation elicited multiple population spikes. The effects of the oxime were presumably not mediated by an antagonism of cholinergic receptors, since they could not be mimicked with cholinergic antagonists like atropine, mecamylamine or gallamine. Further testing of the nature of the HI-6 effect in hippocampal slices in vitro, using a paired antidromic-orthodromic stimulation protocol, showed that HI-6 may interfere with GABAergic inhibition.

Locus coeruleus activation induces perforant path-evoked population spike potentiation in the dentate gyrus of awake rat

In vitro norepinephrine (NE) induces both short- and long-term beta-receptor-mediated potentiation of the perforant path-evoked population spike in the dentate gyrus. NE or locus coeruleus (LC) activation in vivo also produces a beta-receptor dependent potentiation of population spike amplitude in anesthetized rat. Studies of behavioral state modulation of population spike amplitude in awake rats, and in rats depleted of NE, however, have led to the hypothesis that LC-NE activation should act to suppress or reduce population spike amplitude in the dentate gyrus of unanesthetized rat. Using glutamate activation of LC in awake unrestrained rats (n = 12), the present study provides evidence that LC activation in the awake rat does not reduce, but potentiates, population spike amplitude. The potentiation effect was long-lasting (> 25 min) in 50% of the experiments. In addition glutamate ejections in the third lobe of cerebellar rostral vermis produced potentiation of population spike amplitude (n = 3) and population excitatory postsynaptic potential slope. Ejections at sites outside the LC and rostral vermis were ineffective (n = 5). Behavioral effects of glutamate ejection did not predict the occurrence of potentiation. These data support the hypothesis that phasic activation of LC cells is likely to induce short-term, and possibly long-term, potentiation of dentate gyrus throughput in alert animals.

Population spike facilitation in the dentate gyrus following glutamate to the lateral supramammillary nucleus

Glutamate stimulation of the lateral sypramammillary nucleus (SUL) in urethane anaesthetized rats produced a substantial increase in the amplitude of the perforant path-evoked population spike in the dentate gyrus, without affecting the population EPSP slope. One third of the spike enhancements lasted longer than 20 min. These data suggest that SUL afferents provide a mechanism for both short- and long-lasting heterosynaptic modulation of hippocampal throughput.

Stimulation of substantia nigra pars reticulata enhances dentate granule cell excitability

We studied the effects of electrical and chemical stimulation of the substantia nigra (SN) on the dentate granule cell (DGC) response to perforant path stimulation. Studies were carried out in both pentobarbital anesthetized and awake freely moving rats. Chemical stimulation was achieved by microinjection ofN-methyl- d,l-aspartate (NMDA), an excitatory amino acid. Electrical preconditioning stimulation applied to the area of the SN, but not dorsal to SN, increased the excitability of DGCs. Intracerebral microinjection of NMDA into the contralateral SN pars reticulata (SNR), but not into SN pars compacta or cerebral peduncle, also produced a marked and reversible enhancement of DGC excitability. In both instances, the increased DGC excitability consisted of increased amplitude of the perforant path evoked population spike without change in the slope of the population excitatory postsynaptic potential (pEPSP). We interpret the data to indicate that increasing the output of the SNR increases the excitability of the DGCs, a limbic neuronal population regulating information transfer through hippocampal pathways. Together with our previous finding that decreasing the output of SNR suppressed limbic seizures, these data demonstrate that the SNR exerts a powerful influence on limbic system excitability. Delineating the anatomic pathway mediating this influence could provide valuable insight into the mechanisms underlying basal ganglia-limbic interactions in both physiologic and pathologic conditions.

Blockade of norepinephrine-induced long-lasting potentiation in the hippocampal dentate gyrus by an inhibitor of protein synthesis

The mechanism of action of norepinephrine (NE)-induced potentiation of the population spike in the dentate gyrus of hippocampal slices was examined and compared with NE effects in field CA1. NE-induced potentiation was confined to the dentate gyrus, where slices perfused for 30 min with concentrations of NE as low as 5 μM exhibited potentiation of the perforant path evoked population spike. Potentiation began within 15 min, and lasted many hours after NE was washed out. Experiments where slices were pre-incubated with the protein synthesis inhibitor emetine indicated that there are two distinct phases to NE-induced potentiation. The initial short-term NE-induced potentiation (NEP) seen during NE application was not affected by a 30 min pre-incubation with emetine, whereas the long-lasting potentiation (NELLP) which persists after NE washout was completely blocked by emetine at a concentration which we have previously shown to be effective in blocking hippocampal long-term potentiation (LTP). Additional experiments indicated that both phases of NE-induced potentiation were completely blocked by the β-antagonist propranolol and theβ 1-antagonist metoprolol. Furthermore, pre-incubation of slices with the direct-acting adenylate cyclase stimulant forskolin shifted the dose-response curves for both phases of NE-induced potentiation to the left. These results suggest that NE-induced potentiation is probably mediated byβ 1-receptor stimulation of adenylase cyclase. We have previously shown an importance forβ 1-receptor stimulation of adenylate cyclase in the production of LTP in the dentate. Thus, these results demonstrate a number of similarities between hippocampal LTP and NELLP in the dentate gyrus.