cubes

Abstract

Robust synapse loss in striatal spiny projection neurons from transgenic mice overexpressing human wild-type alpha synuclein

J. S-PADILLA1 G. TOMBAUGH1, S. GELMAN1, K. KRETSCHMANNOVA1, H. FERNANDES1, A. GHAVAMI1, J. BELTRAN1, K. CIRILLO1, S. RAMBOZ1
1PsychoGenics, Inc., Paramus, NJ, USA

Alpha-synuclein is a central component of Lewy bodies present in Parkinson’s disease (PD) patients. The consequences of synucleopathy in neuronal function remains unclear and preclinical therapy testing targeting alpha-synuclein are needed. To help identify biomarkers, we utilized whole-cell patch clamp in brain slices to evaluate alterations in synaptic properties in the dorsal striatum from Line 61 transgenic mice overexpressing human wild-type alpha synuclein. Brain slices were prepared from Line 61 mice at ages where they display significant impaired motor behavior and synuclein pathology. Analysis of striatal spiny projection neurons (SPNs) showed a robust decrease in the frequency of miniature excitatory synaptic events in Line 61 compared to wild-type littermates. This phenotype was the same between 2-month and 6-month old Line 61 mice, suggesting a stable readout throughout aging. Analysis of paired-pulse ratio in 6-month old Line 61 corticostriatal synapses revealed no changes in the probability of release, indicating a decrease in excitatory drive in Line 61 is related to synapse loss. The reduction in the frequency of synaptic events was accompanied by a significant increase in the amplitude of synaptic events. This suggests that striatal SPNs from Line 61 underwent synaptic scaling to compensate for the loss of synapses. To further support the synapse loss and scaling phenotype in Line 61, alterations in levels of different synaptic protein markers in the striatum from Line 61 mice will be analyzed using western blotting. Altogether, we have a stable and robust synaptic deficit in the Line 61 model that we can offer for preclinical testing, supporting and translatable to the loss of dendritic spines reported in PD patients and rodent models.

 

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