The nigrostriatal dopamine system of aging GFRα‐1 heterozygous mice: neurochemistry, morphology and behavior

Abstract

Given the established importance of glial cell line-derived neurotrophic factor (GDNF) in maintaining dopaminergic neurotransmitter systems, the nigrostriatal system and associated behaviors of mice with genetic reduction of its high-affinity receptor, GDNF receptor (GFR)α-1 (GFRα-1 +/− ), were compared with wild-type controls. Motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed longitudinally at 8 and 18 months of age. Monoamine concentrations and dopaminergic nerve terminals in the striatum and the number of dopaminergic neurons in the substantia nigra (SN) were assessed. The results support the importance of GFRα-1 in maintaining normal function of the nigrostriatal dopaminergic system, with deficits being observed for GFRα-1 +/− mice at both ages. Motor activity was lower and the stimulatory effects of the DA agonist were enhanced for the older GFRα-1 +/− mice. DA in the striatum was reduced in the GFRα-1 +/− mice at both ages, and tyrosine hydroxylase-positive cell numbers in the SN were reduced most substantially in the older GFRα-1 +/− mice. The combined behavioral, pharmacological probe, neurochemical and morphological measures provide evidence of abnormalities in GFRα-1 +/− mice that are indicative of an exacerbated aging-related decline in dopaminergic system function. The noted deficiencies, in turn, suggest that GFRα-1 is necessary for GDNF to maintain normal function of the nigrostriatal dopaminergic system. Although the precise mechanism(s) for the aging-related changes in the dopaminergic system remain to be established, the present study clearly establishes that genetic reductions in GFRα-1 can contribute to the degenerative changes observed in this system during the aging process.

A dual-hit animal model for age-related parkinsonism

“…The fourth study (Boger, et al, 2009) built upon the third study by further examining the role of inflammation as a possible mediator of the observed effects of a partial Gdnf gene deletion combined with a psychostimulant on DA systems and behavior, using minocyline treatment to reduce inflammation induced by METH administration and/or a partial Gdnf gene deletion (Boger et al, 2007). Two final studies (Zaman, et al, 2008; Boger, et al, 2008) to be discussed were to establish the role of the primary GDNF receptor GFRα1 in the abnormalities noted for the Gdnf +/− mice by including similar studies on Gfrα1 +/− mice.…”

“…Given the established importance of GDNF in maintaining dopaminergic neurotransmitter systems noted above, two additional studies (Zaman, et al, 2008; Boger, et al, 2008) examined the nigrostriatal system and associated behaviors of mice with a genetic reduction of the GDNF high affinity receptor, Gfrα -1 ( Gfrα-1 +/− ) to determine if they displayed abnormalities similar to those noted for the Gdnf +/− mice. In the initial experiment (Zaman, et al, 2008), motor activity and the stimulatory effects of a dopamine (DA) D1 receptor agonist (SKF 82958) were assessed in Gfrα-1 +/− and WT mice at 8 and 18 months-of-age.…”

Biphasic dopamine regulation in mesoaccumbens pathway in response to non-contingent binge and escalating methamphetamine regimens in the Wistar rat

“…While ser19 phosphorylation does not directly regulate TH activity, an increase in vivo may indicate increased neuronal activity (Haycock and Haycock 1991) and may affect the ability of ser40 to be phosphorylated (Bevilaqua et al 2001). TH phosphorylation is also affected by glial cell line-derived neurotrophic factor (GDNF) (Salvatore et al 2004(Salvatore et al , 2009a, and there is an in vivo relationship between GDNF signaling and TH protein expression through GDNF receptor expression (Zaman et al 2008;Pruett and Salvatore 2010). GDNF signaling may be affected in addiction processes (Lu et al 2009), with specific targeting of somatodendritic regions like VTA (Lu et al 2009;Wang et al 2010) and also protects against MA insult (Boger et al 2007).…”

Nigral GFRα1 Infusion in Aged Rats Increases Locomotor Activity, Nigral Tyrosine Hydroxylase, and Dopamine Content in Synchronicity

“…A decrease in GDNF signaling precipitates locomotor impairment while increasing GDNF improves movement. For instance, age-related locomotor impairment is accelerated in mice with heterozygous knockout of either the ligand, GDNF, or its cognate receptor, GDNF family receptor α1 (GFRα1) [4–6]. Conversely, direct delivery of exogenous GDNF improves locomotor functions in animal models of aging [7–11], models of Parkinson’s disease (PD) [12–16], and, in some studies, the PD patient [17, 18].…”