Cellular Mechanisms Of MPTP-mediated Regulation Of Hippocampal Synaptic Transmission And Activity-dependent Plasticity

Parkinson’s disease (PD) represents the second most frequent neurodegenerative disease in the elder population after Alzheimer’s disease. PD patients are characterized by movement disabilities such as tremor, rigidity and bradykinesia. However, cognitive disabilities of PD patients are more and more recognized not only from a scientific point of view but also as serious burden to patients and their care givers. Whereas alterations of memory performance have been described in PD patients, modulation of brain areas is found to be involved in memory formation by environmental or genetic factors that lead to PD onset are from particular interest to understand better the underlying mechanisms of memory decline in PD patients. It is well known that the hippocampus plays a critical role in memory formation. Therefore investigation of hippocampal synaptic transmission in response to putative environmental PD inducing factors was from particular interest. Moreover, the long-term accumulation of potentially neurotoxic compounds, such as pesticides, insecticides or herbicides in the body is suspected to contribute to the slow onset of PD by inducing acute effects on neuron function and later the death of dopaminergic neurons within substantia nigra, ventral tegmental area (VTA) and striatum. MPTP is one type of neurotoxin with the structural similarity as the pesticide paraquat.1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can induce common PD symptoms, including motor dysfunction and non-motor dysfunction. However, present investigations on MPTP mainly focus on the neurodegeneration of dopaminergic neurons and related mechanisms. Although MPTP can induce cognitive dysfunction in rodents and primates, the underlying mechanisms are still elusive. Hence, the first part of this study will explore the acute effects of MPTP on hippocampal synaptic transmission and plasticity and its related mechanisms. The second part will analyze the synaptic transmission and plasticity several days after MPTP systemic application.Part I Acute MPTP application modulates hippocampal synaptic transmission and activity dependent synaptic plasticity via dopamine receptorsParkinson’s disease (PD)-like symptoms and cognitive deficits are inducible by MPTP. Since cognitive abilities, including memory formations also rely on hippocampus, the effects of MPTP on hippocampal function are from interest. Data are presented, which show that MPTP affects hippocampal synaptic transmission and activity-dependent synaptic plasticity of the Schaffer-collateral CA1synapses. Bath-application of MPTP (50-100μM) enhanced AMPA and NMDA receptor-mediated field excitatory postsynaptic potentials (fEPSPs) followed by a decrease to or below baseline level.25μM MPTP enhanced AMPA receptor-mediated field excitatory postsynaptic potentials (AMPAR-fEPSPs) transiently, whereas NMDA receptor-mediated fEPSPs (NMDAR-fEPSPs) were facilitated persistently. To explore the mechanisms underlying MPTP-mediated hippocampal synaptic transmission and activity-dependent plasticity, we chose two different concentrations of MPTP (25M and75μM) in the subsequent experiments. The25μM MPTP mediated transient AMPAR-fEPSP facilitation was antagonized by the selective dopamine D2-like receptor antagonist eticlopride (1μM) and sulpiride (1and40μM). In contrast, the persistent enhancement of NMDAR-fEPSPs was prevented by the dopamine Dl-like receptor antagonist SCH23390(10μM). In addition, we show that MPTP decreased paired-pulse facilitation (PPF) of fEPSPs and mEPSCs frequency. Regarding activity-dependent synaptic plasticity,25μM MPTP transformed short-term potentiation (STP) into a long-term potentiation (LTP) and caused a slow onset potentiation of a non-tetanized synaptic input after induction of LTP in a second synaptic input. This heterosynaptic slow onset potentiation required activation of dopamine D1-like and NMDA-receptors.Regarding to75μM, the MPTP-mediated fEPSP depression was also antagonized by a dopamine D2-like receptor antagonist. A tyrosine phosphatase inhibitor facilitated MPTP-induced fEPSP depression, but a tyrosine kinase inhibitor attenuated the MPTP effect. Moreover, a tyrosine phosphatase dependent DHPG mediated fEPSP depression was occluded by MPTP, whereas a DHPG-induced depression of synaptic transmission facilitated the MPTP-mediated attenuation of fEPSPs.We conclude that acute MPTP application affects basal synaptic transmission by regulation of presynaptic vesicle release probability, and facilitates NMDAR-fEPSPs as well as activity-dependent homo-and heterosynaptic plasticity via dopamine D1-like receptors.Part II In vivo MPTP-meditated hippocampal dopamine deprivation modulates synaptic transmission and activity-dependent synaptic plasticity in acute hippocampal slicesIt is also possible that MPTP may disturb hippocampal memory processing by modulation of dopamine (DA)-and activity-dependent synaptic plasticity. We demonstrate here that intraperitoneal (i.p.) MPTP injection reduces the number of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra (SN) within seven days. Subsequently, the TH expression level in SN and hippocampus and the amount of DA and its metabolite DOPAC in striatum and hippocampus decrease. DA depletion does not alter basal synaptic transmission and changes PPF of fEPSPs only at the30ms inter-pulse interval in acute hippocampal slices. In addition, the induction of LTP is impaired whereas the duration of long-term depression (LTD) becomes prolonged. Since both LTP and LTD depend critically on activation of NMDA and DA receptors, we also tested the effect of DA depletion on NMDA receptor-mediated synaptic transmission. Seven days after MPTP injection, the NMDA receptor-mediated fEPSPs are decreased by about23%. Blocking the NMDA receptor-mediated fEPSP does not mimic the MPTP-LTP. Only co-application of dopamine D1/D5and NMDA receptor antagonists during tetanization resembled the time course of fEPSP potentiation as observed seven days after i.p. MPTP injection. Together, our data demonstrate that MPTP-induced degeneration of DA neurons and the subsequent hippocampal DA depletion alter NMDA receptor-mediated synaptic transmission and activity-dependent synaptic plasticity.In conclusion, we investigate the acute effects or delayed effects of MPTP on hippocampal synaptic transmission and plasticity respectively by using acute or systemic application of MPTP. This study will implicate a lot for elucidation of cognitive dysfunction in Parkinson’s disease and provide different models for screening the therapeutic agents of PD with dementia.