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

HERRERA, MACARENA LORENA; DEZA PONZIO, ROMINA; BASMADJIAN, OSVALDO MARTÍN; OCCHIEPPO, VICTORIA BELÉN; MARCHESE, NATALIA ANDREA; VIRGOLINI, MIRIAM; MOLINA, VICTOR; BELLINI, M.J.; HEREÑÚ, C.

Bilbao

Congreso; 47th European Brain & Behaviour Society Meeting 2017; 2017

European Brain & Behaviour Society

BACKGROUND: Parkinson?s disease (PD) is the second most common neurodegenerative disorder and 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 that PD patients also have non-motor symptoms, where cognitive dysfunction is one of the most common and devastating in this neuropathology. These non-motor symptoms result from the dysfunction of interconnected systems, including the striatum, the neocortex and the hippocampus. Among the different hypothesis related to PD etiology, it is known an abnormal aldehyde dehydrogenase 2 (ALDH2) functionality in neurotransmitter degradation. This leads to the accumulation of neurotoxic metabolites, which have been associated with neuronal cell death and neurodegeneration.OBJECTIVES: 1) determine working memory and spatial memory deficits and its correlation with motor 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 this modelMETHODS: Male Wistar rats were bilaterally injected in dorsal striatum (CPu) with either the neurotoxic (6OHDA rats) or vehicle (SHAM rats). Twenty days after the lesion the animals were tested for working memory with the Y-maze test and short-term spatial memory with a modified version of Y-maze test. Motor function was characterized using locomotor activity with amphetamine administration, stick and hot plate tests. At the end of the study the rats were perfused, their brains fixed and immunohistochemistry performed for TH and ALDH2 in CPu, substantia nigra (SN), dorsal hippocampus (CA1) and prefrontal cortex (PFC) and we identify apoptotic bodies stained with cresyl violet. All data were compared by Student´s t-test and 2-way ANOVA (p<0.05 considered as statistically significant).RESULTS: At behavioral level we observed cognitive dysfunctions in 6-OHDA rats in both working memory and spatial short-term memory (p<0.05) as well. The observed cognitive differences between groups were unrelated to alterations of locomotion since both groups madea 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 neurons in the brain areas involved in nigrostratial pathway (CPu and SN) (p<0.05). Interestingly, we also observed reduction in ALDH2 expression in 6OHDA rats in CPu, SN, CA1 and PFC compared to the SHAM rats (p<0.05). A significant increase in the number of apoptotic bodies was observed in the nigroestriatal pathway.CONCLUSIONS: 1) this early memory impairment occurring at a premotor stage of PD is associated with a partial lesion of the nigrostriatal dopaminergic system; 2) bilateral intra-DLS injection of 6-OHDA was sufficient to cause working memory impairments without locomotor alterations at 20 days post-lesion; 3) decreased ALDH2 expression may be associated to the neurotoxicity and neurodegeneration characteristic of this model; 4) knowledge of this neurodegenerative progression could result in potential new therapeutic strategies, which motivates us to further studies under this experimental model.