A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra

Boger, Heather A.; Middaugh, Lawrence D.; Huang, Peng; Zaman, Vandana; Smith, Andrew C.; Hoffer, Barry J.; Tomac, Andreas C.; Granholm, Ann‐Charlotte

doi:10.1016/j.expneurol.2006.06.006

Cited by 96 publications

(137 citation statements)

References 86 publications

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“…In addition, a toxic METH binge in young adult mice caused a greater reduction in TH-IR in the lateral striatum, DA, and 5-HT markers and motor activity in GDNF ϩ/Ϫ mice than in WT mice at 12 months of age. These data substantiate previous reports that GDNF is an important regulator of DA and motor-system function during aging (Hebert and Gerhardt, 1998;Boger et al, 2006). Furthermore, this study clearly establishes that damage to the nervous system as a consequence of METH may be prolonged and that the absence of immediate behavioral changes does not preclude the possibility that deficits will be manifested at a later time in life.…”

Section: Gdnfsupporting

confidence: 91%

“…In contrast, a twofactor between-groups ANOVA on locomotor activity data at 12 months of age revealed a significant interaction of METH by genotype (F (1,26) ϭ 18.0; p Ͻ 0.001). Comparison of means across the four groups with a one-way ANOVA followed by StudentNeuman-Keuls tests indicated that saline-injected GDNF ϩ/Ϫ mice were significantly less active than age-matched WT saline controls ( p Ͻ 0.01) at 12 months of age, confirming our previous results (Boger et al, 2006). Moreover, 12-month-old GDNF ϩ/Ϫ mice were significantly less active than age-matched WT mice exposed to METH as young adults ( p Ͻ 0.01) (Fig.…”

Section: Meth Effects On Behavior Are Exacerbated In Gdnfsupporting

confidence: 87%

“…Heterozygous offspring are viable and fertile, whereas mice homozygous for the mutant GDNF allele (GDNF Ϫ/Ϫ ) die within 24 h of birth. The mice for this study were bred locally at the Medical University of South Carolina on a C57BL/6J background, weaned, and genotyped as described previously (Boger et al, 2006), according to National Institutes of Health (NIH)-approved protocols. The mice were housed in groups of three or four to a cage and had ad libitum access to food and water.…”

Section: Animals Gdnfmentioning

confidence: 99%

“…Furthermore, at 12 months of age, GDNF ϩ/Ϫ mice have fewer TH-positive neurons in the SN and exhibit less motor activity than wild-type (WT) mice (Boger et al, 2006). Therefore, we hypothesized that METH-induced DAergic toxicity during adolescence would be exacerbated in GDNF ϩ/Ϫ mice and that this "dual hit" would have long-term behavioral and structural consequences in aging mice.…”

Section: Introductionmentioning

confidence: 99%

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Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Boger¹,

Middaugh²,

Patrick³

et al. 2007

J. Neurosci.

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Methamphetamine abuse in young adults has long-term deleterious effects on brain function that are associated with damage to monoaminergic neurons. Administration of glial cell line-derived neurotrophic factor (GDNF) protects dopamine neurons from the toxic effects of methamphetamine in animal models. Therefore, we hypothesized that a partial GDNF gene deletion would increase the susceptibility of mice to methamphetamine neurotoxicity during young adulthood and possibly increase age-related deterioration of behavior and dopamine function. Two weeks after a methamphetamine binge (4 ϫ 10 mg/kg, i.p., at 2 h intervals), GDNF ϩ/Ϫ mice had a significantly greater reduction of tyrosine hydroxylase immunoreactivity in the medial striatum, a proportionally greater depletion of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC) levels in the striatum, and a greater increase in activated microglia in the substantia nigra than wild-type mice. At 12 months of age, methamphetamine-treated GDNF ϩ/Ϫ mice exhibited less motor activity and lower levels of tyrosine hydroxylase-immunoreactivity, dopamine, DOPAC, and serotonin than wild-type mice. Greater striatal dopamine transporter activity in GDNF ϩ/Ϫ mice may underlie their differential response to methamphetamine. These data suggest the possibility that methamphetamine use in young adults, when combined with lower levels of GDNF throughout life, may precipitate the appearance of parkinsonian-like behaviors during aging.

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Section: Gdnfsupporting

confidence: 91%

Section: Meth Effects On Behavior Are Exacerbated In Gdnfsupporting

confidence: 87%

Section: Animals Gdnfmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Boger¹,

Middaugh²,

Patrick³

et al. 2007

J. Neurosci.

View full text Add to dashboard Cite

show abstract

“…Glial cell line-derived neurotrophic factor (GDNF) is a protein that is essential for the maintenance and survival of dopamine (DA) neurons (Boger et al, 2006) and can inhibit microglial activation (Rocha, Cristovão, Campos, Fonseca, & Baltazar, 2012). Additionally, preclinical evidence suggests that infusion of GDNF into the ventral tegmental area (VTA) blocks the acquisition and expression of alcohol-induced conditioned place preference (Barak, Ahmadiantehrani, Kharazia, & Ron, 2011;Barak, Carnicella, Yowell, & Ron, 2011), rapidly reduces alcohol intake (Carnicella, Ahmadiantehrani, Janak, & Ron, 2009, Carnicella, Amamoto, & Ron, 2009Carnicella, Kharazia, Jeanblanc, Janak, & Ron, 2008), and blocks alcohol reinstatement following extinction (Carnicella et al, 2008).…”

Section: Neuroinflammation and Alcohol Dependencementioning

confidence: 99%

Opportunities for the Development of Neuroimmune Therapies in Addiction

Ray

Roche

Heinzerling

et al. 2014

International Review of Neurobiology

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Central nervous system dysfunction in a mouse model of Fa2h deficiency

Potter

Kern

Fullbright

et al. 2011

Glia

122

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Fatty acid 2-hydroxylase (FA2H) is responsible for the synthesis of myelin galactolipids containing hydroxy fatty acid (hFA) as the N-acyl chain. Mutations in the FA2H gene cause leukodystrophy, spastic paraplegia, and neurodegeneration with brain iron accumulation. Using the Cre-lox system, we developed two types of mouse mutants, Fa2h−/− mice (Fa2h deleted in all cells by germline deletion) and Fa2hflox/flox Cnp1-Cre mice (Fa2h deleted only in oligodendrocytes and Schwann cells). We found significant demyelination, profound axonal loss, and abnormally enlarged axons in the CNS of Fa2h−/− mice at 12 months of age, while structure and function of peripheral nerves were largely unaffected. Fa2h−/− mice also exhibited histological and functional disruption in the cerebellum at 12 months of age. In a time course study, significant deterioration of cerebellar function was first detected at 7 months of age. Further behavioral assessments in water T-maze and Morris water maze tasks revealed significant deficits in spatial learning and memory at 4 months of age. These data suggest that various regions of the CNS are functionally compromised in young adult Fa2h−/− mice. The cerebellar deficits in 12-month-old Fa2hflox/flox Cnp1-Cre mice were indistinguishable from Fa2h−/−mice, indicating that these phenotypes likely stem from the lack of myelin hFA-galactolipids. In contrast, Fa2hflox/flox Cnp1-Cre mice did not show reduced performance in water maze tasks, indicating that oligodendrocytes are not involved in the learning and memory deficits found in Fa2h−/− mice. These findings provide the first evidence that FA2H has an important function outside of oligodendrocytes in the CNS.

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A partial GDNF depletion leads to earlier age-related deterioration of motor function and tyrosine hydroxylase expression in the substantia nigra

Cited by 96 publications

References 86 publications

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Long-Term Consequences of Methamphetamine Exposure in Young Adults Are Exacerbated in Glial Cell Line-Derived Neurotrophic Factor Heterozygous Mice

Opportunities for the Development of Neuroimmune Therapies in Addiction

Central nervous system dysfunction in a mouse model of Fa2h deficiency

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