Dataset Information

Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice.

ABSTRACT: α-Synuclein (α-syn)-induced neurotoxicity has been generally accepted as a key step in the pathogenesis of Parkinson's disease (PD). Microtubule-associated protein tau, which is considered second only to α-syn, has been repeatedly linked with PD in association studies. However, the underlying interaction between these two PD-related proteins in vivo remains unclear. To investigate how the expression of tau affects α-syn-induced neurodegeneration in vivo, we generated triple transgenic mice that overexpressed α-syn A53T mutation in the midbrain dopaminergic neurons (mDANs) with different expression levels of tau. Here, we found that tau had no significant effect on the A53T α-syn-mediated mDANs degeneration. However, tau knockout could modestly promote the formation of α-syn aggregates, accelerate the severe and progressive degeneration of parvalbumin-positive (PV⁺) neurons in substantia nigra pars reticulata (SNR), accompanied with anxiety-like behavior in aged PD-related α-syn A53T mice. The mechanisms may be associated with A53T α-syn-mediated specifically successive impairment of N-methyl-d-aspartate receptor subunit 2B (NR2B), postsynaptic density-95 (PSD-95) and microtubule-associated protein 1A (MAP1A) in PV⁺ neurons. Our study indicates that MAP1A may play a beneficial role in preserving the survival of PV⁺ neurons, and that inhibition of the impairment of NR2B/PSD-95/MAP1A pathway, may be a novel and preferential option to ameliorate α-syn-induced neurodegeneration.

SUBMITTER: Jiao L

PROVIDER: S-EPMC8353962 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:The substantia nigra pars reticulata (SNr), where the basal ganglia (BG) direct and indirect pathways converge, contains among the highest expression of cannabinoid receptor type 1 (CB1r) in the brain. Hence, SNr is an ideal locus to study pathway interactions and cannabinergic modulations. The objective of this study was to characterize the effects of systemic injections of the CB1r agonist (CP55940) on the balanced activity of the direct/indirect pathways in the SNr and its associated behaviors. To this aim, we recorded somatosensory and pathway-specific representations in the spiking activity of the SNr of male rats under CP55940. CB1r activation mainly decreased the inhibitory, potentially direct pathway component while sparing the excitatory, potentially indirect pathway component of somatosensory responses. As a result, cutaneous stimulation produced unbalanced responses favoring increased SNr firing rates, suggesting a potential locus for cannabinergic motor-related effects. To test this hypothesis, we implemented an ad hoc behavioral protocol for rats in which systemic administration of CP55940 produced kinematic impairments that were completely reverted by nigral injections of the CB1r antagonist (AM251). Our data suggest that cannabinoid-related motor effects are associated with unbalanced direct/indirect pathway activations that may be reverted by CB1r manipulation at the SNr.SIGNIFICANCE STATEMENT The cannabinergic system has been the target of multiple studies to master its potential use as a therapeutic agent. However, significant advances have been precluded by the lack of mechanistic explanations for the variety of its desirable/undesirable effects. Here, we have combined electrophysiological recordings, pharmacological and optogenetic manipulations, and an ad hoc behavioral protocol to understand how basal ganglia (BG) is affected by cannabinoids. We found that cannabinoids principally affect inhibitory inputs, potentially from the direct pathway, resulting in unbalanced responses in the substantia nigra pars reticulata (SNr) and suggesting a mechanism for the cannabinoid-related slowness of movements. This possibility was confirmed by behavioral experiments in which cannabinoid-related slowness of purposeful movements was reverted by cannabinoid receptor type 1 (CB1r) manipulations directly into the SNr.

Project description:ObjectiveGenetic Absence Epilepsy Rats from Strasbourg (GAERS) show a resistance to secondary generalization of focal limbic seizures evoked by kindling. The substantia nigra pars reticulata (SNR) is involved in the propagation and modulation of seizures in kindling. We first examined the role of the SNRanterior and SNRposterior subregions in the resistance to the development of kindling in GAERS. Subsequently, to determine whether kindling resistance relates to differential sensitivity of γ-aminobutyric acid γ-aminobutyric acid (GABA)ergic or dopaminergic SNR neurons to kindling, we studied the effects of kindling-inducing stimulations on parvalbumin (PRV; GABAergic neuron marker) or tyrosine hydroxylase (TH; dopaminergic neuron marker) immunoreactivity (ir), respectively, in GAERS and in nonepileptic control (NEC) Wistar rats that lack kindling resistance.MethodsAdult male GAERS were implanted with a stimulation electrode in the amygdala, and bilateral injection cannulas for lidocaine or saline injection (30 min before each kindling stimulation until the animals reached three stage 5 seizures or the 22 stimulations) into the SNRanterior or SNRposterior . In another experiment, PRV-ir in SNRanterior and SNRposterior and TH-ir in SNRposterior only were densitometrically compared in GAERS-SHAM, NEC-SHAM GAERS-STIM, and NEC-STIM animals (6 kindling stimulations).ResultsBilateral SNRposterior infusions of lidocaine eliminated the kindling resistance and resulted in stage 5 generalized motor seizures in all kindled rats. Bilateral lidocaine infusions in the SNRanterior failed to alter the kindling resistance in GAERS. PRV-ir in the SNRposterior was unaltered in GAERS-STIM but increased in NEC-STIM group. Cellular TH-ir in the SNRposterior significantly increased by kindling stimulations in both NEC-STIM and GAERS-STIM groups.SignificanceThe kindling resistance in GAERS is mediated by the SNRposterior in a lidocaine-sensitive manner. The insensitivity to kindling stimulation of PRV-ir in SNRposterior of GAERS but not NEC rats, implicate GABAergic SNRposterior neurons in kindling resistance. In contrast, the observed stimulation-specific increase in TH-ir in the SNRposterior is unrelated to kindling resistance.

Dataset Information

Tau knockout exacerbates degeneration of parvalbumin-positive neurons in substantia nigra pars reticulata in Parkinson's disease-related α-synuclein A53T mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets