Alterations in corticostriatal synaptic plasticity in mice overexpressing human α-synuclein

doi:10.1016/j.neuroscience.2009.01.021

Neuroscience

Volume 159, Issue 2, 17 March 2009, Pages 501-513

https://doi.org/10.1016/j.neuroscience.2009.01.021 Get rights and content

Abstract

Most forms of Parkinson's disease (PD) are sporadic in nature, but some have genetic causes as first described for the α-synuclein gene. The α-synuclein protein also accumulates as insoluble aggregates in Lewy bodies in sporadic PD as well as in most inherited forms of PD. The focus of the present study is the modulation of synaptic plasticity in the corticostriatal pathway of transgenic (Tg) mice that overexpress the human α-synuclein protein throughout the brain (ASOTg). Paired-pulse facilitation was detected in vitro by activation of corticostriatal afferents in ASOTg mice, consistent with a presynaptic effect of elevated human α-synuclein. However basal synaptic transmission was unchanged in ASOTg, suggesting that human α-synuclein could impact paired-pulse facilitation via a presynaptic mechanism not directly related to the probability of neurotransmitter release. Mice lacking α-synuclein or those expressing normal and A53T human α-synuclein in tyrosine hydroxylase-containing neurons showed, instead, paired-pulse depression. High-frequency stimulation induced a presynaptic form of long-term depression solely in ASOTg striatum. A presynaptic, N-methyl-d-aspartate receptor-independent form of chemical long-term potentiation induced by forskolin (FSK) was enhanced in ASOTg striatum, while FSK-induced cAMP levels were reduced in ASOTg synaptoneurosome fractions. Overall the results suggest that elevated human α-synuclein alters presynaptic plasticity in the corticostriatal pathway, possibly reflecting a reduction in glutamate at corticostriatal synapses by modulation of adenylyl cyclase signaling pathways. ASOTg mice may recapitulate an early stage in PD during which overexpressed α-synuclein dampens corticostriatal synaptic transmission and reduces movement.

Section snippets

Animals

WT and ASOTg littermate mice overexpressing human α-synuclein under the control of the mouse Thy-1 promoter were generated previously on the C57BL/6×DBA2 genetic background (Rockenstein et al., 2002). Non-Tg α-synuclein control mice (Snca^+/+) and knock-out (Snca^−/−) littermates lacking α-synuclein gene expression were generated previously in the 129×SvEv genetic background (Cabin et al., 2002). Tg mice expressing either normal (wt) or mutant A53T human α-synuclein in tyrosine-hydroxylase

Normal glutamatergic synaptic transmission in ASOTg striatum

Elevated expression of human α-synuclein protein in ASOTg relative to WT brain was confirmed by Western immunoblotting using an antibody that recognizes both exogenous human and endogenous mouse α-synuclein (Fig. 1A). Based on density values (mean±SEM) for α-synuclein normalized to β-actin, human α-synuclein is elevated many fold relative to endogenous mouse α-synuclein in ASOTg forebrain (WT, 0.05±0.0, n=4 mice; ASOTg, 1.19±0.03, n=4 mice; P<0.05) consistent with an initial report (Rockenstein

Short-term presynaptic plasticity is altered in the corticostriatal pathway of ASOTg

The central finding from this study is that ubiquitous overexpression of human α-synuclein in mouse brain significantly alters both short-term and long-term presynaptic plasticity in the corticostriatal pathway. Results from short-term synaptic plasticity studies of corticostriatal slices from both α-synuclein over-expressing mice and knock-out mice showed that only elevated amounts of human α-synuclein reliably induced paired-pulse facilitation in the dorsolateral region of the striatum. In

Acknowledgments

Supported by the Center for Gene Environment Studies in Parkinson's disease (CGEP) at UCLA (NIH U54 ES012078) (M.S.L., J.B.W.), The UDALL Center for Excellence in the Study of Parkinson's Disease (NIH NS 38367) (M.S.L., J.B.W.), and a Faculty Research Grant from the UCLA Academic Senate (J.B.W.). Many thanks to Gloria Klapstein, Damian Cummings, Carlos Cepeda, Véronique André, Emily Jocoy, Nanping Wu and other members of Mike Levine's lab as well as Tom O'Dell for their critical feedback and

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Cellular NeuroscienceAlterations in corticostriatal synaptic plasticity in mice overexpressing human α-synuclein

Abstract

Section snippets

Animals

Normal glutamatergic synaptic transmission in ASOTg striatum

Short-term presynaptic plasticity is altered in the corticostriatal pathway of ASOTg

Acknowledgments

Neuron

Neuron

Prog Neurobiol

Neurobiol Aging

Neuroscience

Trends Neurosci

Neuron

Neuroscience

Neuroscience

Neuron

Neuroscience

Neurobiol Dis

J Chem Neuroanat

Neuron

J Neurosci Methods

Cell

Trends Neurosci

Brain Res Mol Brain Res

Neurobiol Dis

Neuron

Neurotoxicology

Neuroscience

Neurosci Lett

Neuron

Brain Res

Neuron

Neuroscience

Neurobiol Dis

Neuron

Anandamide regulates postnatal development of long-term synaptic plasticity in the rat dorsolateral striatum

J Neurosci

Functional state of corticostriatal synapses determines their expression of short- and long-term plasticity

Synapse

LRRK2 low-penetrance mutations (Gly201Ser) and risk alleles (Gly2385Arg)-linking familial and sporadic Parkinson's disease

Neurochem Res

Synaptic vesicle depletion correlates with attenuated synaptic responses to prolonged repetitive stimulation in mice lacking α-synuclein

J Neurosci

Long-term synaptic depression in the striatum: physiological and pharmacological characterization

J Neurosci

Long-term potentiation in the striatum is unmasked by removing the voltage-dependent magnesium block of the NMDA receptor channels

Eur J Neurosci

RIM1alpha is required for presynaptic long-term potentiation

Nature

Differential electrophysiological properties of dopamine D1 and D2 receptor-containing striatal medium-sized spiny neurons

Eur J Neurosci

Double-knockout mice for α- and β-synucleins: effect on synaptic functions

Proc Natl Acad Sci U S A

Decreased probability of neurotransmitter release underlies striatal long-term depression and postnatal development of corticostriatal synapse

Proc Natl Acad Sci U S A

Excitatory synaptic transmission in neostriatal neurons: regulation by cAMP-dependent mechanisms

J Neurosci

Identification of synaptic terminals of thalamic or cortical origin in contact with distinct medium-size spiny neurons in the rat neostriatum

J Comp Neurol

Cellular Neuroscience
Alterations in corticostriatal synaptic plasticity in mice overexpressing human α-synuclein