Variability in neuronal expression of dopamine receptors and transporters in the substantia nigra

Background: Parkinsons disease (PD) patients have increased susceptibility to impulse control disorders. Recent studies suggest that alterations in dopamine receptors in the midbrain underlie impulsive behaviours, and that more impulsive individuals, including patients with PD, exhibit an increase in occupancy of their midbrain dopamine receptors. The cellular location of dopamine receptor subtypes and transporters within the human midbrain may therefore have important implications for the development of impulse control disorders in PD.Methods: The localisation of the dopamine receptors (D1-5) and dopamine transporter proteins in the upper brainstem of elderly adult humans (n=8) was assessed using single immunoperoxidase and double immunofluorescence (with tyrosine hydroxylase to identify dopamine neurons). The relative amount of protein expressed in dopamine neurons from different regions was assessed by comparing their relative immunofluorescent intensities.Results: The midbrain dopamine regions associated with impulsivity (medial nigra and ventral tegmental area, VTA) expressed less dopamine transporter on their neurons than other midbrain dopamine regions. Medial nigral dopamine neurons expressed significantly greater amounts of D1 and D2 receptors, and vesicular monoamine transporter, than VTA dopamine neurons. Conclusions: The heterogeneous pattern of dopamine receptors and transporters in the human midbrain suggests that the effects of dopamine and dopamine agonists are likely to be non-uniform. The expression of excitatory D1 receptors on nigral dopamine neurons in midbrain regions associated with impulsivity, and their variable loss as seen in PD, may be of particular interest for impulse control

Endogenous progesterone levels and frontotemporal dementia: Modulation of TDP-43 and Tau levels in vitro and treatment of A315T TARDBP mouse model

Clinical variants of Frontotemporal dementia (FTD) include semantic dementia (SD) and progressive nonfluent aphasia (PNFA). Together with the closely related disorders FTD with motor neurone disease (FTD-MND), corticobasal syndrome (CBS) and progressive supranuclear palsy (PSP), they constitute a major cause of young onset dementia. The steroid hormone progesterone (PROG) has an important role as a neurosteroid with potent neuroprotective and promyelination properties. In a case-control study of serum samples (39 FTD, 91 controls), low serum PROG was associated with FTD overall (Exp(B) = 2.6, adjusted p = 0.019). In our subgroup analysis, low PROG levels were significantly associated with FTD-MND (N = 12, Exp(B) = 5.0, adjusted p = 0.022) and CBS (N = 10, Exp(B) = 5.9, adjusted p = 0.017), but not with the other subgroups. PROG levels of > 195 pg/mL were significantly correlated with lower disease severity (Frontotemporal dementia rating Scale) for CBS patients (N = 6, standardized &#946; = -0.92, adjusted p = 0.0002). In the human neuroblastoma SK-N-MC cell line, exogenous progesterone (9300 to 93,000 pg/mL) had a significant effect on overall tau and nuclear TDP-43 levels, reducing total tau levels by approximately 1.5 fold (p < 0.05) and increasing nuclear TDP-43 by 1.7 to 2.0 fold (p < 0.05). Finally, elevation of serum PROG to approximately 6000 pg/mL in an Ala315Thr TARDBP mutant mouse model significantly reduced the rate of loss of locomotor control (adjusted p = 0.033) in PROG treated compared with placebo mice. The PROG treatment did not significantly increase survival of the mice, and may be due to the limitation of the transgenic mouse to accurately model TDP-43 mediated neurodegeneration. Nonetheless, our clinical, cellular and animal data provide strong evidence that PROG may be a valid therapy for specific related disorders of FTD