Cellular Dysfunction in a Neurotoxic Model of Parkinson´s Disease: Implications in Memory and Motor Systems

HERRERA, MACARENA LORENA; DEZA PONZIO, ROMINA; BASMADJIAN, OSVALDO MARTIN; OCCHIEPPO, VICTORIA BELÉN; MARCHESE, NATALIA ANDREA; VIRGOLINI, MIRIAM BEATRIZ; MOLINA, VICTOR ALEJANDRO; BELLINI, MARÍA JOSÉ; HEREÑÚ, CLAUDIA BEATRIZ

Bilbao

Congreso; 47 European Brain y behaviour Society Meeting; 2017

European Brain y behaviour Society

BACKGROUND: Parkinson?s disease (PD) is the second most common neurodegenerative disorderand is characterized pathologically by the loss of dopaminergic neurons in the substantia nigra.Although motor symptoms are the main clinical features of PD, increasing evidence has shown thatPD patients also have non-motor symptoms, where cognitive dysfunction is one of the mostcommon and devastating in this neuropathology. These non-motor symptoms result from thedysfunction of interconnected systems, including the striatum, the neocortex and the hippocampus.Among the different hypothesis related to PD etiology, it is known an abnormal aldehydedehydrogenase 2 (ALDH2) functionality in neurotransmitter degradation. This leads to theaccumulation of neurotoxic metabolites, which have been associated with neuronal cell death andneurodegeneration.OBJECTIVES: 1) determine working memory and spatial memory deficits and its correlation withmotor function; 2) correlate these behavioral changes with the loss of dopaminergic neurons; 3)evaluate ALDH2 expression in a 6OHDA animal model; 4) identify neuronal apoptosis in thismodelMETHODS: Male Wistar rats were bilaterally injected in dorsal striatum (CPu) with either theneurotoxic (6OHDA rats) or vehicle (SHAM rats). Twenty days after the lesion the animals weretested for working memory with the Y-maze test and short-term spatial memory with a modifiedversion of Y-maze test. Motor function was characterized using locomotor activity withamphetamine administration, stick and hot plate tests. At the end of the study the rats wereperfused, their brains fixed and immunohistochemistry performed for TH and ALDH2 in CPu,substantia nigra (SN), dorsal hippocampus (CA1) and prefrontal cortex (PFC) and we identifyapoptotic bodies stained with cresyl violet. All data were compared by Student´s t-test and 2-wayANOVA (p<0.05 considered as statistically significant).RESULTS: At behavioral level we observed cognitive dysfunctions in 6-OHDA rats in bothworking memory and spatial short-term memory (p<0.05) as well. The observed cognitivedifferences between groups were unrelated to alterations of locomotion since both groups made a similar (p>0.05) distance traveled and horizontal wire mesh pole and hot plate performance.At cellular level, 6OHDA treatment induced a reduction in TH positive dopaminergic neuronsin the brain areas involved in nigrostratial pathway (CPu and SN) (p<0.05). Interestingly, wealso observed reduction in ALDH2 expression in 6OHDA rats in CPu, SN, CA1 and PFCcompared to the SHAM rats (p<0.05). A significant increase in the number of apoptotic bodieswas observed in the nigroestriatal pathway.CONCLUSIONS: 1) this early memory impairment occurring at a premotor stage of PD isassociated with a partial lesion of the nigrostriatal dopaminergic system; 2) bilateral intra-DLSinjection of 6-OHDA was sufficient to cause working memory impairments without locomotoralterations at 20 days post-lesion; 3) decreased ALDH2 expression may be associated to theneurotoxicity and neurodegeneration characteristic of this model; 4) knowledge of thisneurodegenerative progression could result in potential new therapeutic strategies, which motivatesus to further studies under this experimental model.