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Normal nigrostriatal innervation but dopamine dysfunction in mice carrying hypomorphic tyrosine hydroxylase alleles
Author(s) -
Althini Susanna,
Bengtsson Henrik,
Usoskin Dmitry,
Söderström Stine,
Kylberg Annika,
Lindqvist Eva,
Chuva de Sousa Lopes Susana,
Olson Lars,
Lindeberg Jonas,
Ebendal Ted
Publication year - 2003
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.10606
Subject(s) - tyrosine hydroxylase , substantia nigra , dopamine , catecholaminergic , biology , striatum , dopamine transporter , aromatic l amino acid decarboxylase , endocrinology , medicine , nigrostriatal pathway , dopaminergic , vesicular monoamine transporter 2
We investigated the use of the mouse tyrosine hydroxylase (TH) gene to drive knock‐in constructs in catecholaminergic neurons. Two targeting constructs representing truncated forms of either of the BMP receptors ALK‐2 or BMPR‐II preceded by an internal ribosome entry site (IRES) were introduced into the 3′ untranslated region of TH. An frt‐flanked neomycin‐resistance (neo r ) cassette was placed in the 3′ end of the targeting constructs. Mice homozygous for the knock‐in alleles showed various degrees of hypokinetic behavior, depending mainly on whether the neo r cassette was removed. In situ hybridization and immunohistochemistry showed that TH mRNA and protein were variously down‐regulated in these mouse strains. Reduced levels of dopamine and noradrenalin were found in several brain areas. However, number and morphology of neurons in substantia nigra and their projections to striatum appeared normal in the neo r ‐positive TH hypomorphic mice as examined by markers for L‐aromatic amino acid decarboxylase and the dopamine transporter. Elimination of the neo r cassette from the knock‐in alleles partially restored TH and dopamine levels. The present neo r ‐positive TH hypomorphic mice show that nigrostriatal innervation develops independently of TH and should find use as a model for conditions of reduced catecholamine synthesis, as seen in, for example, L‐dihydroxyphenylalanine‐responsive dystonia/infantile parkinsonism. © 2003 Wiley‐Liss, Inc.

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