Mutations in the genes coding for ␣-synuclein and parkin cause autosomal-dominant and autosomal-recessive forms of Parkinson's disease (PD), respectively. ␣-Synuclein is a major component of Lewy bodies, the proteinaceous cytoplasmic inclusions that are the pathological hallmark of idiopathic PD. Lewy bodies appear to be absent in cases of familial PD associated with mutated forms of parkin. Parkin is an ubiquitin E3 ligase, and it may be involved in the processing and/or degradation of ␣-synuclein, as well as in the formation of Lewy bodies. Here we report the behavioral, biochemical, and histochemical characterization of double-mutant mice overexpressing mutant human A53T ␣-synuclein on a parkin null background. We find that the absence of parkin does not have an impact on the onset and progression of the lethal phenotype induced by overexpression of human A53T ␣-synuclein. Furthermore, all major behavioral, biochemical, and morphological characteristics of A53T ␣-synuclein-overexpressing mice are not altered in parkin null ␣-synucleinoverexpressing double-mutant mice. Our results demonstrate that mutant ␣-synuclein induces neurodegeneration independent of parkin-mediated ubiquitin E3 ligase activity in nondopaminergic systems and suggest that PD caused by ␣-synuclein and parkin mutations may occur via independent mechanisms.

Attention deficit hyperactivity disorder (ADHD) is characterized by hyperactivity, inattention, and impulsivity. The coloboma mouse model of ADHD exhibits profound hyperactivity. To determine whether coloboma mice exhibit other signs of ADHD, we assessed latent inhibition as a test of attention, and impulsivity in a delayed reinforcement paradigm. Latent inhibition was present in control mice but was disrupted in coloboma mice. Coloboma mice also exhibited impaired performance on the delayed reinforcement task and were not able to wait as long as control mice to obtain the greater reinforcer. Because norepinephrine mediates hyperactivity in coloboma mice, we examined the role of norepinephrine in disrupted latent inhibition and impulsivity. Reduction of norepinephrine with DSP-4 (N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride) restored latent inhibition but did not ameliorate impulsivity. In summary, coloboma mice exhibit hyperactivity, inattention as determined by latent inhibition, and impulsivity, and norepinephrine mediates hyperactivity and inattention but not impulsivity in these mice.

The neonatal 6-OHDA-lesioned rat, coloboma mouse, DAT-KO mouse, and spontaneously hypertensive rat (SHR) models all bear a phenotypic resemblance to ADHD in that they express hyperactivity, inattention, and/or impulsivity. The models also illustrate the heterogeneity of ADHD: the initial cause (chemical depletion or genetic abnormality) of the ADHD-like behaviors is different for each model. Neurochemical and behavioral studies of the models indicate aberrations in monoaminergic neurotransmission. Hyperdopaminergic neurotransmission is implicated in the abnormal behavior of all models. Norepinephrine has a dual enhancing/inhibitory role in ADHD symptoms, and serotonin acts to inhibit abnormal dopamine and norepinephrine signaling. It is unlikely that symptoms arise from a single neurotransmitter dysfunction. Rather, studies of animal models of ADHD suggest that symptoms develop through the complex interactions of monoaminergic neurotransmitter systems.

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