MPTP modulates hippocampal synaptic transmission and activity‐dependent synaptic plasticity via dopamine receptors

Abstract

J. Neurochem. (2012) 122, 582–593. Abstract Parkinson’s disease (PD)‐like symptoms and cognitive deficits are inducible by 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP). Since cognitive abilities, including memory formations rely also on hippocampus, we set out to clarify the effects of MPTP on hippocampal physiology. We show that bath‐application of MPTP (25 μM) to acute hippocampal slices enhanced AMPA receptor‐mediated field excitatory postsynaptic potentials (AMPAr‐fEPSPs) transiently, whereas N‐methyl‐D‐aspartate (NMDA) receptor‐mediated fEPSPs (NMDAr‐fEPSPs) were facilitated persistently. The MPTP‐mediated transient AMPAr‐fEPSP facilitation was antagonized by the dopamine D2‐like receptor antagonists, eticlopride (1 μM) and sulpiride (1 and 40 μM). In contrast, the persistent enhancement of NMDAr‐fEPSPs was prevented by the dopamine D1‐like receptor antagonist SCH23390 (10 μM). In addition, we show that MPTP decreased paired‐pulse facilitation of fEPSPs and mEPSCs frequency. Regarding activity‐dependent synaptic plasticity, 25 μM 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. We conclude that acute MPTP application affects basal synaptic transmission by modulation of presynaptic vesicle release and facilitates NMDAr‐fEPSPs as well as activity‐dependent homo‐ and heterosynaptic plasticity under participation of dopamine receptors.

Rapamycin upregulates glutamate transporter and IL-6 expression in astrocytes in a mouse model of Parkinson’s disease

“…We then examined the effects of MPTP on hippocampal synaptic plasticity in acute brain slices. In contrast to the results of a previous study in which 25  μ M MPTP increased the baseline in an unsubmerged recording chamber, 16 we demonstrated that 25  μ M MPTP did not increase the baseline and instead partially blocked the LTP in a submerged chamber (MPTP: 132±4%, n =6 versus vehicle: 158±6%, n =8, P <0.01) (Supplementary Figure S1d). Interestingly, 200 nM rapamycin alone had no effect on the LTP (152±7%, n =8), but this low dose of rapamycin could prevent the effects of MPTP on the LTP (160±9%, n =8) (Supplementary Figure S1e).…”

Pramipexole restores depressed transmission in the ventral hippocampus following MPTP-lesion

“…No previous studies have differentiated between dHip and vHip22454647. Further other studies found an enhancement of fEPSP when MPTP was applied to the hippocampus in the bath23. The theoretical model explains LTP as a mechanism for short term modification of the synapse and in the longer term a mechanism for stimulating spine formation.…”

“…8) where a short-term lesion causes an enhanced LTP as direct result of the loss of dopamine innervation23. There is a discordance amongst the studies that have examined LTP following MPTP lesion, which is most likely caused by different experimental approaches e.g.…”

“…Some studies found no decrease in DA levels after MPTP administration20 while others showed a depletion after multiple MPTP injections2122. Despite this uncertainty, MPTP intoxication has been shown to impair several types of memory and also damages synaptic transmission in mice2223.…”

Potentiation of Schaffer-Collateral CA1 Synaptic Transmission by eEF2K and p38 MAPK Mediated Mechanisms

“…The preparation of acute hippocampal slices closely followed previously published methodologies (Behnisch et al, 2011; Zhu et al, 2012; Huang et al, 2015). Briefly, after anaesthetization with isoflurane, brains were immersed in ice-cold ACSF (95% O 2 /5% CO 2 and composition in mM: 124 NaCl, 2.5 KCl, 2.5 CaCl 2 , 2 MgCl 2 ⋅6 H 2 O, 1.25 KH 2 PO 4 , 10 glucose, 26 NaHCO 3 , pH 7.3–7.4).…”