Severely impaired hippocampal neurogenesis associates with an early serotonergic deficit in a BAC a-synuclein transgenic XXXX model of @entity191 .

@entity1 @entity308 @entity8095 @entity66 @entity935 @entity191 @entity148 @entity750 @entity1251 @entity35 @entity71069 @entity12148
UNASSIGNED: @entity191 ( @entity191 ) is a @entity66 , involving several monoaminergic neurotransmitter systems resulting in a broad range of motor and non-motor symptoms. Pathological hallmarks of @entity191 are the loss of dopaminergic neurons and the accumulation of @entity8095 , however also being present in the serotonergic raphe nuclei early in the disease course. The dysfunction of the serotonergic system projecting to the hippocampus may contribute to early non-motor symptoms such as @entity148 and @entity308 . The adult hippocampal dentate gyrus (DG), a unique niche of the forebrain continuously generating new neurons, may particularly present enhanced susceptibility towards accumulating @entity8095 levels. The underlying molecular mechanisms in the context of neuronal maturation and survival of new-born neurons are yet not well understood. To characterize the effects of overexpression of @entity1 full-length @entity8095 on hippocampal cellular and synaptic plasticity, we used a recently generated BAC @entity8095 transgenic @entity35 model showing important features of @entity191 such as widespread and progressive @entity8095 aggregation pathology, @entity935 loss and age-dependent motor decline. At the age of four months, thus prior to the occurrence of the motor phenotype, we observed a profoundly impaired dendritogenesis of neuroblasts in the hippocampal DG resulting in severely reduced survival of adult new-born neurons. Diminished neurogenesis concurred with a serotonergic deficit in the hippocampus as defined by reduced levels of @entity750 ( @entity750 ) 1B receptor, decreased @entity750 neurotransmitter levels, and a loss of serotonergic nerve terminals innervating the DG/ @entity1251 subfield, while the number of serotonergic neurons in the raphe nuclei remained unchanged. Moreover, @entity8095 overexpression reduced proteins involved in vesicle release, in particular @entity12148 and @entity71069 ), in conjunction with an altered ultrastructural architecture of hippocampal synapses. Importantly, BAC @entity8095 @entity35 showed an early @entity148 -like phenotype consisting of reduced exploratory behavior and feeding. Taken together, these findings imply that accumulating @entity8095 severely affects hippocampal neurogenesis paralleled by impaired @entity750 neurotransmission prior to the onset of aggregation pathology and overt motor deficits in this transgenic @entity35 model of @entity191 .
