Altered neurotransmitter receptor expression in transgenic mouse models of Huntington's disease

Author:

Cha Jang-Ho J.1,Frey Ariel S.1,Alsdorf Stephen A.1,Kerner Julie A.1,Kosinski Christoph M.1,Mangiarini Laura2,Penney John B.1,Davies Stephen W.3,Bates Gillian P.2,Young Anne B.1

Affiliation:

1. 1Department of Neurology, Massachusetts General Hospital, Fruit Street, Boston, MA 02114, USA

2. Medical and Molecular Genetics, GKTMedical and Dental School, Kings College, 8th Floor, Guy'sTower, London SE1 9RT, UK

3. Department of Anatomy and Developmental Biology, University College London, Gower Street, LondonWC1E 6BT, UK

Abstract

Alterations in neurotransmitter receptors are a pathological hallmark of the neurodegeneration seen in Huntington's disease (HD). However, the significance of these alterations has been uncertain, possibly reflecting simply the loss of brain cells. It is not known for certain whether the alteration of neurotransmitter receptors occurs before the onset of symptoms in human HD. Recently we developed transgenic mice that contain a portion of a human HD gene and develop a progressive abnormal neurological phenotype. Neurotransmitter receptors that are altered in HD (receptors for glutamate, dopamine, acetylcholine and adenosine) are decreased in the brain of transgenic mice, in some cases before the onset of behavioural or motor symptoms. In transgenic mice, neurotransmitter receptor alterations occur before neuronal death. Further, receptor alterations are selective in that certain receptors, namely N -methyl-D-aspartate and γ-aminobutyric acid receptors, are unaltered. Finally, receptor decreases are preceded by selective decreases in the corresponding mRNA species, suggesting the altered transcription of specific genes. These results suggest that (i) receptor decreases precede, and therefore might contribute to, the development of clinical symptoms, and (ii) altered transcription of specific genes might be a key pathological mechanism in HD.

Publisher

The Royal Society

Subject

General Agricultural and Biological Sciences,General Biochemistry, Genetics and Molecular Biology

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