Cannabinoid receptor messenger RNA levels decrease in a subset of neurons of the lateral striatum, cortex and hippocampus of transgenic Huntington's disease mice.

Abstract

One of the earliest changes, at the molecular level, that occurs in human Huntington's disease patients is reduction in cannabinoid receptor ligand binding in the substantia nigra pars reticulata compared to neurologically normal controls. The loss of cannabinoid receptor binding is thought to occur early in or prior to the development of Huntington's disease neuropathology. We wish to determine whether cannabinoid receptor messenger RNA levels were altered in a mouse model of Huntington's disease. Transgenic mice hemizygous for the promoter sequence and exon 1 of the human Huntington's disease gene exhibit a progressive neurological phenotype with many of the features of Huntington's disease. This neurological phenotype develops in the absence of neural degeneration making these mice a model system to dissociate changes related to cell dysfunction from changes related to cell loss. We examine the steady-state levels and cellular distribution of the brain-specific cannabinoid receptor messenger RNA by northern blot and in situ hybridization. The cannabinoid receptor messenger RNA was expressed throughout the striatum, cortex and hippocampus of wild-type mice. At four and five weeks of age, there was no difference in the distribution of the cannabinoid receptor messenger RNA between the wild-type and transgenic Huntington's disease mice. At six, seven, eight and 10 weeks of age, however, the Huntington's disease mice exhibit reduced levels of cannabinoid receptor messenger RNA in the lateral striatum compared to age-matched controls. The Huntington's disease mice also showed a loss of cannabinoid receptor messenger RNA within a subset of neurons in the cortex and hippocampus. We did not observe any difference in the expression of cannabinoid receptor between the wild-type and Huntington's disease mice throughout Ammon's horn of the hippocampus or in the medial striatum. The decrease in cannabinoid receptor messenger RNA levels preceded the development of the Huntington's disease phenotype and neuronal degeneration and, therefore, these transgenic mice model early cellular changes observed in human patients. Our results demonstrate that the single copy cannabinoid receptor gene is subjected to cell-specific and time-dependent regulation of the steady-state level of its gene product as a result of the expression of the Huntington's disease gene. As the endogenous cannabinoid receptor agonist, anandimide, has been shown to modulate dopamine neurotransmission within the basal ganglia, the loss of cannabinoid receptors may contribute to the development of motor symptoms or cognitive decline or both seen in Huntington's disease patients.