Characterization of striatum-mediated behavior and neurochemistry in the DJ-1 knock-out rat model of Parkinson's disease.

ABSTRACT

The recently developed DJ-1 knockout (KO) rat models the DJ-1 (or PARK7) loss-of-function mutation responsible for one form of early-onset familial Parkinson's disease (PD). Prior studies demonstrate that DJ-1 KO rats present progressive dopamine (DA) cell body degeneration in the substantia nigra pars compacta between 4 and 8 months of age. Furthermore, as some motor deficits emerge before the significant loss of DA cells, this mutation may yield a period of DA neuron dysfunction preceding cell death that may also contribute to cognitive impairments in early PD. However, cognitive functions subserved by corticostriatal circuitry, as well as additional alterations to the neurochemistry of monoamine systems, are largely uncharacterized in the DJ-1 KO rat. We therefore assessed a variety of striatally-mediated behavioral tasks, as well as the integrity of dopamine and serotonin systems, in male DJ-1 KO rats and wild-type (WT) controls at 4, 6, and 8 months of age. We demonstrate that DJ-1 KO rats exhibited motor impairments, but have intact goal-directed control over behavior in an appetitive instrumental learning task. Further, preprotachykinin mRNA expression, a post-synaptic indicator of DA signaling, was significantly decreased in 4-month DJ-1 KO rats, while DA transporter binding in the dorsal striatum did not differ between genotypes at any of the ages examined. Striatal tyrosine hydroxylase levels were significantly increased in 8-month DJ-1 KO rats and tended to be higher than WT at 4 and 6 months. Lastly, serotonin transporter binding was increased in the medial and orbitofrontal cortices of 4-month old DJ-1 KO rats. These results suggest that the nigrostriatal dopaminergic and prefrontal serotoninergic systems are altered early in the progression of DJ-1 KO pathology, despite no overt loss of the DA innervation of the striatum, and thus may be associated with early alterations in the functions of corticostriatal systems.