Mice transgenic for exon 1 of Huntington's disease: properties of cholinergic and dopaminergic pre-synaptic function in the striatum.

In Huntington's disease (HD), neuronal loss is most prominent in the striatum leading to emotional, cognitive and progressive motor dysfunction. The R6/2 mice, transgenic for exon 1 of the HD gene, develop a neurological phenotype with similarities to these features of HD. In striatal tissue, electrically evoked release of tritiated acetylcholine (ACh) and dopamine (DA) were compared in wild-type (WT) and R6/2 mice. In R6/2 mice, the evoked release of ACh, its M2 autoreceptor-mediated maximum inhibition and its dopamine D2 heteroreceptor-mediated maximum inhibition was diminished to 51%, 74% and 87% of controls, respectively. Also, the activities of choline acetyltransferase and of synaptosomal high-affinity choline uptake decreased progressively with age in these mice. In the DA release model, however, electrical stimulation elicited equal amounts of [3H]-DA both in WT and R6/2 mice. Moreover, high-affinity DA uptake into striatal slices was similar in WT and R6/2 mice. In order to confirm these findings in vivo, intrastriatal levels of extracellular DA were measured by intracerebral microdialysis in freely moving mice: striatal DA levels were found to be equal in WT and R6/2 mice. In conclusion, in the transgenic R6/2 mice changes occur mainly in striatal cholinergic neurones and their pre-synaptic modulation, but not in the dopaminergic afferent terminals. Whether similar events also contribute to the pathogenesis of HD in humans has to be established.

Impaired glutamate transport and glutamate-glutamine cycling: downstream effects of the Huntington mutation.

The pathogenesis of Huntington's disease is still not completely understood. Several lines of evidence from toxic/non-transgenic animal models of Huntington's disease suggest that excitotoxic mechanisms may contribute to the pathological phenotype. Evidence from transgenic animal models of Huntington's disease, however, is sparse. To explore potential alterations in brain glutamate handling we studied transgenic mice expressing an N-terminal fragment of mutant huntingtin (R6/2). Intracerebral microdialysis in freely moving mice showed similar extracellular glutamate levels in R6/2 and littermate controls. However, partial inhibition of glutamate transport by L-trans-pyrrolidine-2,4-dicarboxylate (4 mM) disclosed an age-dependent increase in extracellular glutamate levels in R6/2 mice compared with controls, consistent with a reduction of functional glutamate transport capacity. Biochemical studies demonstrated an age-dependent downregulation of the glial glutamate transporter GLT-1 mRNA and protein, resulting in a progressive reduction of transporter function. Glutamate transporters other than GLT-1 were unchanged. In addition, increased extracellular glutamine levels and alterations to glutamine synthetase immunoreactivity suggested a perturbation of the glutamate-glutamine cycle. These findings demonstrate that the Huntington's disease mutation results in a progressively deranged glutamate handling in the brain, beginning before the onset of symptoms in mice. They also provide evidence for a contribution of excitotoxicity to the pathophysiology of Huntington's disease, and thus Huntington's disease may be added to the growing list of neurodegenerative disorders associated with compromised glutamate transport capacity.

Extracellular glutamate and other metabolites in and around RG2 rat glioma: an intracerebral microdialysis study.

The current study determined the extracellular content of glutamate, 10 additional amino acids, lactate, glucose and some antioxidants in a rodent model of malignant glioma, its peritumoral space and the adjacent cortex. RG2 tumors were induced in the right frontal cortex of Fischer-344 rats (n = 10) by a standardized procedure to obtain a maximum sagittal tumor width of 3-4 mm diameter. After confirmation of tumor growth and localization by contrast enhanced MRI three microdialysis probes were implanted simultaneously in the cortex: at the tumor implantation site (tumor), 2 mm caudally, brain around tumor (BAT) and 4 mm caudally (cortex) to the site of implantation. Dialysate concentrations of glutamate were increased 3.9-fold in tumor and 2-fold in BAT compared with cortex. Glycine was elevated 11.4-fold in tumor and 2.6-fold in BAT. Lactate was increased 1.7-fold in tumor, 1.2-fold in BAT. Levels of glucose, ascorbic acid and uric acid were not significantly different in tumor, BAT and cortex. The increased dialysate levels of glutamate and glycine in the peritumoral space may contribute to impaired neuronal function and epileptiform activity associated with this tumor type in humans.

Regional cerebral blood flow in peritumoral brain edema during dexamethasone treatment: a xenon-enhanced computed tomographic study.

OBJECTIVE: Regional cerebral flood flow (rCBF) in peritumoral brain edema is assumed to be decreased because of increased interstitial pressure. Impaired blood flow might lead to local hypoxia, altered metabolism, and disturbed ion homeostasis, thus causing neurological sequelae. Steroid treatment is thought to positively influence the sequelae of brain edema. We aimed to determine the rCBF in peritumoral edema in humans receiving dexamethasone treatment and the relationship of rCBF to global CBF. METHODS: We measured rCBF in 11 patients with untreated anaplastic gliomas or glioblastomas that were World Health Organization Grade III or IV restricted to one hemisphere with significant peritumoral edema who were receiving a standard dose of dexamethasone. rCBF was determined using stable xenon-enhanced computed tomography in a stereotactic frame. Edema was defined both by means of actual histology (stereotactic biopsies) and by imaging criteria. RESULTS: rCBF in peritumoral edema was decreased by 32% as compared with contralateral normal white matter. In each patient, this reduction was linearly related to blood flow in nonaffected white matter and cortex. The flow ratio in the different compartments was 1 (edema):1.5 (contralateral white matter):2.7 (contralateral cortex). Absolute perfusion values in contralateral cortex (means +/- standard deviations) (29.9+/-7.1 ml/100 g/min) and contralateral white matter (16.1+/-3.7 ml/100 g/min) were significantly decreased as well. CONCLUSION: Our study demonstrated that rCBF in peritumoral brain edema during steroid treatment is still decreased and is in a range in which it may cause neurological sequelae. Also, global CBF was decreased in all patients.