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Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption.

ABSTRACT: Transgenic (Tg) mouse models of Parkinson's disease (PD) generated to date have primarily been designed to overexpress human alpha-synuclein (alpha-syn) to recapitulate PD-like motor impairments as well as PD-like nigrostriatal degeneration and alpha-syn pathology. However, cognitive impairments and cortical alpha-syn pathology are also common in PD patients. To model these features of PD, we created forebrain-specific conditional Tg mice that overexpress human wild type (WT) or A53T mutant alpha-syn. Here we show that both WT and A53T mutant alpha-syn lead to massive degeneration of postmitotic neurons in the hippocampal dentate gyrus (DG) during postnatal development, with hippocampal synapse loss as evidenced by reduced levels of pre- and postsynaptic markers. However, when mutant and WT alpha-syn expression was repressed until the Tg mice were mature postnatally and then induced for several months, no hippocampal neuron loss was observed. These data imply that developing neurons are more vulnerable to degenerate than mature neurons as a consequence of forebrain WT and mutant alpha-syn overexpression.

SUBMITTER: Lim Y

PROVIDER: S-EPMC2812632 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption.

Lim Youngshin Y Kehm Vicky M VM Li Chi C Trojanowski John Q JQ Lee Virginia M-Y VM

Experimental neurology 20091013 1

Transgenic (Tg) mouse models of Parkinson's disease (PD) generated to date have primarily been designed to overexpress human alpha-synuclein (alpha-syn) to recapitulate PD-like motor impairments as well as PD-like nigrostriatal degeneration and alpha-syn pathology. However, cognitive impairments and cortical alpha-syn pathology are also common in PD patients. To model these features of PD, we created forebrain-specific conditional Tg mice that overexpress human wild type (WT) or A53T mutant alph ...[more]

PMID: 19833127

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Project description:Parkinson’s disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse. Parkinson’s disease (PD), the second most frequent neurodegenerative disorder at old age, can be caused by elevated expression, or the A53T mutation, of the presynaptic protein alpha-synuclein (SNCA). PD is characterized pathologically by the preferential vulnerability of the dopaminergic nigrostriatal projection neurons. Here, we used two mouse lines overexpressing human A53T-SNCA around ages 6 and 18 months and studied striatal dysfunction in the absence of neurodegeneration to understand early disease mechanisms. High pressure liquid chromatography analysis of striatal neurotransmitter content demonstrated that dopamine (DA) levels correlated directly with the level of expression of SNCA, an observation also observed in SNCA deficient mice. In the striatum of aged A53TSNCA overexpressing mice, where DA levels were elevated, a paradoxical upregulation of dopamine receptors DRD1A and DRD2 was detected by immunoblots and autoradiography, findings compatible with the notion of abnormal vesicle release. Extensive transcriptome studies via microarrays and quantitative real-time RT-PCR validation of altered Homer1, Cb1, Atf2 and Pde7b transcript levels indicated a progressive reduction in the postsynaptic DA response. As functional consequences, long term depression was absent in corticostriatal slices from aged transgenic mice and an insidious decrease of spontaneous locomotor activity of these animals was found in open field tests. Taken together, the dysfunctional neurotransmission and decreased synaptic plasticity seen in the A53T-SNCA overexpressing mice reflects early functional changes within the basal ganglia resulting from synucleinopathy prior to frank neurodegeneration. Thus, preclinical stages of PD may be modeled in this mouse.

Dataset Information

Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption.

Publications

Forebrain overexpression of alpha-synuclein leads to early postnatal hippocampal neuron loss and synaptic disruption.

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