Perforant Path-dentate Gyrus Pathway Research Articles

Zhengtian Pills accelerated long term potentiation both in Schaffer collateral -CA1 and perforant path-dentate gyrus synapses

ObjectiveTo investigate the effects of Zhengtian Pills (ZTP) on long term potentiation (LTP) both in Schaffer-CA1 in vitro and perforant path-dentate gyrus (PP-DG) synapses in vivo. MethodsSprague-Dawley rats were randomly divided into five groups: control, positive control, migraine model, low-, and high-dose ZTP groups. Glyceryl trinitrate (10 mg/kg) was injected subcutaneously to make migraine rat model. Flunarizine (0.9 mg/kg) was set as positive control. Extracellular recording technique in vivo was used to record the effects of ZTP on LTP of PP-DG pathway in anesthetized rats; Using extracellular recording technique in vitro, the effects of ZTP on LTP of Schaffer Collateral-CA1 pathway in rat hippocampal slices were investigated. ResultsCompared to the control group, ZTP (1.08 g/kg) significantly enhanced population spike amplitude in PP-DG pathway; Glyceryl trinitrate (10 mg/kg) significantly reduced population spike amplitude in PP-DG pathway; Neither ZTP (0.54 g/kg) nor Flunarizine (0.9 mg/kg) had significant effects on LTP in PP-DG pathway. Compared to the model group, ZTP (1.08 g/kg), ZTP (0.54 g/kg), and flunarizine (0.9 mg/kg) significantly enhanced population spike amplitude in PP-DG pathway. Compared to the control group, ZTP (1.08 g/kg) significantly enhanced field excitatory postsynaptic potential (fEPSP) slope in Schaffer Collateral-CA1 pathway; Glyceryl trinitrate (10 mg/kg) significantly reduced fEPSP slope in Schaffer Collateral-CA1 pathway; Neither ZTP (0.54 g/kg) nor flunarizine (0.9 mg/kg) significant effects on LTP in Schaffer Collateral-CA1 pathway, Compared to the model group, ZTP (1.08 g/kg), ZTP (0.54 g/kg), and Flunarizine (0.9 mg/kg) had significantly enhanced fEPSP slope in Schaffer Collateral-CA1 pathway. ConclusionCombined with the previous study, the results gave a clue that the effects of ZTP on TRPV1 and hippocampal LTP or their interactions could be the important molecular mechanisms of ZTP acting as migraine and headache medication.

The impact of zotepine onthe excitatory synaptic response and long-term potentiation in the hippocampus of rabbits

：Objective To observe theimpact of zotepine on the excitatory synaptic response and long term potentiation (LTP) ofdentate gyrus neurons.Methods Male rabbits ( n = 20) weighting about 2.5 ～ 3.5 kg were divided into four groups randomly ( n = 5 ): control,zotepine 1.0, zotepine 2.0 and zotepine 5.0.To each rabbit,there were 60 results during120 min.Population spike(PS) amplitude and excitory postsynaptic potential (EPSP) slopewere used to be the indexes of the excitatory synaptic response of dentate gyrusneurons.The sequence was base response ( at the beginning), intraperitoneal injection of0.5ml dimethylsulfoxide or 0.5ml zotepine-dimethylsulfoxide solution ( 1.0,2.0,5.0 mg/kgof zotepine dosage) ( after 30 min) and titanic stimulation (after 90 min).Results To 4groups,the PS amplitude and EPSP slope after single stimuli were not significantlydifferent from those before single stimuli.In control group, the PS amplitude and EPSPslope after titanic stimulation[(0.68 ± 0.052)mV and(0.633 ± 0.024 )mV/ms] weresignificantly different from those before injection[(0.266 ±0.008) mV and(0.246 ±0.010)mV/ms] (P＜0.05 ～0.01 ) ,and LTP wereinduced.LTP were not induced after titanic stimulation in group zotepine 1.0,2.0 and5.0.After titanic stimulation, the PS amplitude and EPSP slope in group zotepine5.0[(0.277 ±0.008)mV and(0.296 ±0.007) mV/ms] were significantly different from those ingroup control(P＜ 0.05).Conclusion Zotepine had little effect on the excitatory synaptic responseof dentate gyrus neurons after single stimuli in perforant path, while it blocked theinduction of LTP in perforant path-dentate gyrus pathway. Key words: Zotepine; Perforant path; Dentate gyrus; Long-termpotentiation

Increase in extracellular dopamine levels during clozapine-induced potentiation in the hippocampal dentate gyrus of chronically prepared rabbits

We previously found that 20 mg/kg clozapine i.p. potentiated the excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulation of the perforant path in chronically prepared rabbits. We called this phenomenon clozapine-induced potentiation and proved that it was an NMDA receptor-mediated event. This potentiation is presumably related to clozapine's clinical effect on negative symptoms and cognitive dysfunctions in schizophrenia. In the present study, to investigate the mechanisms underlying clozapine-induced potentiation, we examined whether extracellular dopamine and 5-HT levels changed during the potentiation by using a microdialysis technique in the dentate gyrus. The extracellular concentrations of dopamine and 5-HT levels were measured every 5 min during all experiments. Extracellular 5-HT levels did not change, but dopamine levels eventually increased significantly during clozapine-induced potentiation. The increase in the dopamine levels occurred almost simultaneously with the induction of clozapine-induced potentiation. These results suggest that clozapine-induced potentiation is at least partly attributable to a dopamine-mediated potentiation of excitatory synaptic transmission. The present study implies that such phenomena occur also in the perforant path-dentate gyrus pathway.

Effects of zotepine on excitatory synaptic responses in the perforant path–dentate gyrus pathway in chronically prepared rabbits

The effects of an atypical antipsychotic drug, zotepine, were examined on excitatory synaptic responses elicited in the dentate gyrus by single electrical stimulation of the perforant path and the induction of long-term potentiation in this pathway in chronically prepared rabbits. Doses of 1.0, 2.0 and 5.0 mg/kg of zotepine intraperitoneally injected had virtually no effect on the excitatory synaptic responses. However, these doses of zotepine dose dependently suppressed the induction of long-term potentiation. According to our previous studies, these results indicate that the effects of zotepine are different from those of the other atypical antipsychotic drugs, clozapine, but are rather similar to those of a typical antipsychotic drug, haloperidol and the 5-HT-dopamine receptor antagonist, risperidone. Furthermore, the zotepine-induced blockade of long-term potentiation induction may be associated with drug-induced cognitive dysfunction such as memory disturbance.

Effects of risperidone, an atypical antipsychotic drug, on excitatory synaptic responses in the perforant path–dentate gyrus pathway in chronically prepared rabbits

The effects of an atypical antipsychotic drug, risperidone, were examined on excitatory synaptic responses in the dentate gyrus by single electrical stimulations to the perforant path and the induction of long-term potentiation (LTP) in this pathway in chronically prepared rabbits. Any of 0.5, 1.0 and 2.0 mg/kg doses of risperidone intraperitoneally injected had virtually no effect on the excitatory synaptic responses. However, these three doses of risperidone dose-dependently suppressed the LTP induction.

Brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling without affecting paired-pulse measures of neuronal inhibition in adult rats

Kindling is an animal model of human temporal lobe epilepsy in which excitability in limbic structures is permanently enhanced by repeated stimulations. Kindling also increases the expression of nerve growth factor, brain-derived neurotrophic factor, and brain-derived neurotrophic factor receptor messenger RNAs in both the hippocampus and cerebral cortex and causes structural changes in the hippocampus including hilar hypertrophy. We have recently shown that intraventricular nerve growth factor infusion enhances the development of kindling, whereas blocking nerve growth factor activity retards amygdaloid kindling. Furthermore, we have shown that nerve growth factor protects against kindling-induced hilar hypertrophy. The physiological role of brain-derived neurotrophic factor in kindling is not as clear. Acute injection of brain-derived neurotrophic factor increases neuronal excitability and causes seizures, whereas chronic brain-derived neurotrophic factor infusion in rats slows hippocampal kindling. In agreement with the latter, we show here that intrahilar brain-derived neurotrophic factor infusion delays amygdala and perforant path kindling. In addition, we show that brain-derived neurotrophic factor, unlike nerve growth factor, does not protect against kindling-induced increases in hilar area. To test the hypothesis that brain-derived neurotrophic factor suppresses kindling by increasing inhibition above normal levels, we performed paired-pulse measures in the perforant path–dentate gyrus pathway. Brain-derived neurotrophic factor infused into the hippocampus had no effect on the stimulus intensity function (input/output curves); there was also no significant effect on paired-pulse inhibition. We then kindled the perforant path 10 days after the end of brain-derived neurotrophic factor treatment. Once again, kindling was retarded, showing that the brain-derived neurotrophic factor effect is long-lasting. These results indicate that prolonged in vivo infusion of brain-derived neurotrophic factor reduces, rather than increases, excitability without increasing inhibitory neuron function, at least as assessed by paired-pulse protocols. This effect may be mediated by long-lasting effects on brain-derived neurotrophic factor receptor regulation.

( R, S)- α-methyl-4-carboxyphenylglycine (MCPG) fails to block long-term potentiation under urethane anaesthesia in vivo

The effects of the metabotropic glutamate receptor antagonist ( R, S)- α-methyl-4-carboxyphenyl-glycine (MCPG) on the induction of long-term potentiation (LTP) in the dentate gyrus were examined under urethane anaesthesia in vivo. In experiment 1, bilateral intraventricular infusion of either 20 mM or 200 mM ( R, S)-MCPG (5μl each side) failed to block LTP in the perforant path-granule cell projection, relative to vehicle-infused controls; 30 mM d-AP5 (5 μl each side) infused in the same way as MCPG completely blocked LTP. Experiment 2, in which the contralateral perforant path-dentate gyrus pathway was used as a non-tetanized control, revealed that slight baseline changes induced by MCPG infusion were transient; again no block of LTP was obtained. The efficacy of mGluR blockade was confirmed in experiment 3, in which MCPG antagonized an increase in spontaneous activity induced by (1 S,3 R)-1-aminocyclopentane- l,3-dicarboxyric acid (ACPD). In experiment 4, significant depotentiation was induced by low frequency stimulation (5 Hz for 1 min) given 2 min after high frequency tetanization, but MCPG remained ineffective in blocking LTP after a second tetanus. In experiment 5, increasing the period of low frequency stimulation from 1 to 10 min produced greater depotentiation, but still did not unmask an MCPG-sensitive component of LTP. These experiments fail to support a role for mGluRs in the induction of LTP in the dentate gyrus under urethane anaesthesia in vivo, nor do they support the idea that a metabotropic switch controlling sensitivity to MCPG is reset by depotentiation.

Clozapine-induced potentiation of synaptic responses in the perforant path-dentate gyrus pathway in chronically prepared rabbits

To examine the contribution of N-methyl- d-aspartate (NMDA) receptors in the mechanisms underlying the action of antipsychotics, we investigated the effects of a representative atypical antipsychotic, clozapine (CLZ), on the induction of long-term potentiation (LTP) in the perforant path-dentate gyrus pathway in 15 chronically prepared rabbits. Eventually, neither low (10 mg/kg) nor high (20 mg/kg) doses of CLZ intraperitoneally injected had any effects on LTP induction. However, the high dose CLZ always potentiated the ordinary synaptic responses induced by single stimulations before the LTP induction. The present study indicates a new finding, the presence of ‘CLZ-induced potentiation’, although it needs further investigation whether NMDA receptors contribute to this potentiation.

Carbamazepine-induced blockade of induction of long-term potentiation in the perforant path-dentate gyrus pathway in chronically prepared rabbits

We investigated the effects of a representative anti-epileptic or anti-psychotic drug, carbamazepine (CBZ), on the induction of long-term potentiation (LTP) in the perforant path-dentate gyrus pathway in 15 chronically prepared rabbits. Pharmacokinetically injected low-dose CBZ, which produced steady serum levels of 2.2–3.3 μg/ml (mean ± S.D. 2.85 ± 0.40), variably affected the induction of LTP, blocking it or showing almost no effect. The high-dose CBZ, which produced steady serum levels of 6.5–8.6 μg/ml (8.01 ± 0.87), always blocked the induction of LTP. These results indicate that CBZ dose-dependently blocks the induction of LTP. The possible mechanisms underlying this blockade are discussed, especially in association with the possible inhibitory action of CBZ on N- methyl- d-aspartate (NMDA) receptors.

Haloperidol-induced blockade of induction of long-term potentiation in perforant path-dentate gyrus pathway in chronically prepared rabbits

We investigated the effects of the representative neuroleptic and dopamine receptor antagonist haloperidol (HPD) on the induction of long-term potentiation (LTP) or on the previously induced LTP in the perforant path-dentate gyrus pathway in chronically prepared rabbits. The IP HPD injection of 0.8 mg/kg blocked the induction of LTP when it was given before LTP-inducing tetanic stimulations, although this dose showed virtually no effect on the baseline control responses in the perforant path-dantate gyrus pathway to single shocks. However, neither 0.8-mg/kg nor 1.6-mg/kg HPD doses affected the previously induced LTP. The possible mechanisms underlying these results, notably the HPD-induced blockade of LTP induction, are discussed, especially in association with the inhibitory action of HPD on calmodulin-mediated events rather than dopaminergic function.