The cortical lesion of Huntington's disease: Further neurochemical characterization, and reproduction of some of the histological and neurochemical features by N‐methyl‐D‐aspartate lesions of rat cortex

Abstract

Huntington's disease is a progressive neurodegenerative disease in which the basal ganglia are preferentially affected. Recent evidence, however, suggests involvement of the cerebral cortex as well, with sparing of neurochemically defined subsets of gamma-aminobutyric acid (GABA)-ergic interneurons. In the present study, we examined changes in concentrations of the amino acid neurotransmitters GABA, glutamate, and aspartate in nine cortical regions from 23 patients with advanced Huntington's disease and 12 control brains. GABA concentrations were significantly increased in eight of the nine regions, consistent with a sparing of GABAergic local circuit neurons in the context of progressive cortical atrophy. Small but significant increases in glutamate were found in six of the nine regions, while aspartate levels were generally unaffected. Striate cortex (Brodmann's area 17) showed the most profound increases in GABA and glutamate. We also investigated the effects of powdering the excitotoxins N-methyl-D-aspartate (NMDA) or kainic acid onto the dura of rats. The resulting lesions were examined at 1 week and 6 months. The NMDA-induced lesions showed striking sparing of parvalbumin-positive neurons (a subset of GABAergic interneurons), and this sparing was reflected in neurochemical measurements of GABA; kainic acid lesions failed to display this selectivity. Somatostatin, cholecystokinin, and vasoactive intestinal polypeptide concentrations were spared by the NMDA-induced lesions, and substance P levels were significantly increased. These results provide evidence that NMDA excitotoxic lesions of cerebral cortex can produce a selective pattern of neuronal damage similar to that which occurs in Huntington's disease.

R6/2 neurons with intranuclear inclusions survive for prolonged periods in the brains of chimeric mice

“…The major site of neuron loss in HD is the striatal part of the basal ganglia, and it is specifically the loss of striatal projection neurons that accounts for the progressive movement disorder (Vonsattel et al, 1985;De La Monte et al, 1988;Hedreen et al, 1991;Storey et al, 1992). The disease process, however, does not affect striatal projection neurons uniformly, since enkephalinergic striatal projection neurons and their terminals in the external pallidal segment (GPe) and substance P (SP)-containing striatal projection neurons and their terminals in the substantia nigra are affected earlier in the disease than are SPcontaining striatal projection neurons and their terminals in the internal pallidal segment (GPi) (Reiner et al, 1988; …”

Inhibition of Metabotropic Glutamate Receptor Signaling by the Huntingtin-binding Protein Optineurin

“…Glutamate-mediated neurotoxicity has been postulated to play an important role in the pathogenesis and excitotoxic neuronal cell loss in HD (5)(6)(7)(8)(9). The receptors for glutamate are classified into two types: ionotropic and metabotropic (10).…”

Visual perception in prediagnostic and early stage Huntington's disease

“…Rosas et al (2002) reported MR measured thinning of the cortical ribbon, which was most severe in posterior brain regions, including dorsal visual cortex (Brodmann areas 17, 18, and 19). Storey et al (1992) reported an increase in gamma-aminobutyric acid (GABA) concentrations in multiple cortical regions, with the largest increases in striate cortex (area 17). GABAergic neurons seem to play an important role in visual processing in ani- mals (Egelhaaf et al, 1990;Leventhal et al, 2003) and humans (Giersch & Herzog, 2004).…”

“…Structural MRI assessment has shown reductions of grey matter (Fennema-Notestine et al, 2004;Mühlau et al, 2007;Rosas et al, 2002) and white matter in the occipital cortex (Beglinger et al, 2005;FennemaNotestine et al, 2004). Post-mortem increases in gammaaminobutyric acid (GABA) concentrations in the cortex, with the largest increases in the striate cortex, have also been reported (Storey et al, 1992). Visual perceptual impairments have been reported in other neurodegenerative disorders.…”