A Pitx3-deficient developmental mouse model for fine motor, olfactory, and gastrointestinal symptoms of Parkinson's disease.

Parkinson's disease (PD) is characterized by the selective death of substantia nigra pars compacta (SNpc) dopaminergic neurons and includes both motor and non-motor symptoms. While numerous models exist for the study of typical PD motor deficits, fewer exist for non-motor symptoms. Previous studies have shown that a Pitx3-/- mouse model (aphakia or ak mouse) has specific developmental failure of the dopaminergic neuron population in the SNpc and that it can be used for the study of PD-related gross motor dysfunction as well as cognitive functional deficits. It remains unclear whether the aphakia mouse, both male and female, might also be used to model fine motor deficits and for additional studies of non-motor deficits associated with PD. Here, using an extensive battery of behavioral tests, we demonstrate that the aphakia mouse shows both gross and fine motor functional deficits compared with control mice. Furthermore, aphakia mice show deficits of olfactory function in buried pellet, odor discrimination and odor habituation/dishabituation tests. We also found that aphakia mice suffer from gastrointestinal dysfunction (e.g., longer whole gut transit time and colon motility deficits), suggesting that the mutation also affects function of the gut-brain axis in this animal model. Moreover, our data demonstrate that in the aphakia mouse, L-DOPA, the gold standard PD medication, can rescue both gross and fine motor function deficits but neither olfactory nor gastrointestinal symptoms, a pattern much like that seen in PD patients. Altogether, this suggests that the aphakia mouse is a suitable model for fine motor, olfactory and gastrointestinal behavioral studies of PD as well as for the development of novel disease-modifying therapeutics. SIGNIFICANCE STATEMENT: While several animal models are available to study the major motor symptoms of PD, there are fewer that replicate non-motor symptoms, which constitute a major source of morbidity for patients. Moreover, available models often require manipulations resulting in sudden massive cell loss and inflammation, both of which may interfere with understanding of the direct effects of dopaminergic neuronal loss in the SNpc. We describe a model of congenital SNpc cell deficiency in a Pitx3-/- mouse and characterize it with a battery of behavioral tests suggesting that it closely mimics non-motor as well as motor symptoms of PD, providing a useful insight into the effects of the nigrostriatal dopamine deficit. Taken together, these data suggest that the ak mouse represents a useful model to study dopaminergic system function for both motor and non-motor symptoms of PD.

Nitric Oxide Induces a Janus Kinase-1-Dependent Inflammatory Response in Primary Murine Astrocytes.

Nitric oxide (NO) is a versatile free radical that has been implicated in many biological processes (i.e., vasodilation, neurotransmission, and smooth muscle relaxation). High levels of NO, such as those produced by inducible NO synthase, are associated with innate immunity as well as tissue damage and disease pathology. Previous studies have characterized many stimuli that lead to NO production following central nervous system (CNS) infection, ischemia, and during neurodegeneration, but less is known about the effects of NO on the CNS resident astrocytes. Previously, excessive NO has been shown to impair protein folding leading to endoplasmic reticulum (ER) stress and initiation of the unfolded protein response. Previous studies have shown that ER stress drives activation of protein kinase R-like ER kinase (PERK) and Janus kinase-1 (JAK1) leading to inflammatory gene expression. We hypothesized that NO drives inflammatory processes within astrocytes through a similar process. To test this, we examined the effects of exogenous NO on primary cultures of murine astrocytes. Our data suggest that NO promotes a pro-inflammatory response that includes interleukin-6 and several chemokines. Our data show that NO induces phosphorylation of eukaryotic initiation factor 2 alpha; however, this and the inflammatory gene expression are independent of PERK. Knockdown of JAK1 using small interfering RNA reduced the expression of inflammatory mediators. Overall, we have identified that NO stimulates the integrated stress response and a JAK1-dependent inflammatory program in astrocytes.Summary statement: Murine astrocytes in culture respond to NO with increased expression of stress and inflammatory genes. The inflammatory stress response is independent of the ER stress-activated kinase PERK and is, in part, mediated by JAK1.