Deafferentation-induced abnormal neurofilament phosphorylation in red nucleus neurones.

Hippocampal deafferentation has been proposed as a pathogenetic mechanism for neurofibrillary tangle (NFT) formation in human mesolimbocortical dementia. We previously developed a rodent model of hippocampal deafferentation involving bilateral destructive lesions of the ventrotegmental area (VTA), septum of the medial forebrain and entorhinal cortex combined with pharmacological inhibition of serotonin 5-HT2 and dopamine D1 receptors. Unexpectedly, we observed an alteration in phosphorylated neurofilament protein immunoreactivity and argyrophilia in magnocellular neurones of the red nucleus.

Neuronal argyrophilia and phosphorylated neurofilament accumulation secondary to deafferentation.

This work tests the hypothesis that deafferentation caused by experimental brain lesions leads to the appearance of perikaryal argyrophilia and the accumulation of phosphorylated cytoskeletal proteins which are potential precursors for neurofibrillary tangle formation. Destructive lesions of the ventral tegmental area, the septum of the medial forebrain and the entorhinal cortex, when combined with systemic administration of a D-1 dopamine receptor antagonist, produced transsynaptic changes in neurons of the hippocampal formation in the midbrain. Abnormally phosphorylated neurofilament protein was demonstrated immunohistochemically in the cytoplasm of mesencephalic pyramidal neurons, particularly in the red nucleus.

Denervation induced abnormal phosphorylation in hippocampal neurons.

This study demonstrates that combined dopaminergic and cholinergic denervation of the hippocampus results in the appearance of morphologically altered, Tau reactive, apical dendrites of granule cells in the rat dentate gyrus. The denervated granule cells and their apical dendrites also display immunoreactivity to a mitogen-activated protein kinase, ERK-1, and also evidence of abnormal phosphorylation of these dendrites as revealed by SMI-31 immunoreactivity. Dopaminergic denervation alone also causes mitogen activated protein kinase reactivity without the Tau-reactive apical dendrities.

Immunoreactive changes resulting from dopaminergic denervation of the dentate gyrus of the rat hippocampal formation.

The hypothesis that dopaminergic denervation is a factor in the development of hippocampal neurofibrillary tangles was tested in the rat with bilateral stereotaxic 6-hydroxydopamine (6-OHDA) lesions of the ventral tegmental area (VTA). This led to the postsynaptic appearance of cytoplasmic immunoreactivity to ubiquitin in neurons of the dentate gyrus. An additional postsynaptic morphologic abnormality was seen when the animals were pretreated with the D1 dopaminergic antagonist SCH 23390 and the VTA lesions were combined with septal lesions affecting cholinergic and GABAergic neurons projecting to the dentate gyrus.

Analysis of the prion protein gene in thalamic dementia.

Thalamic degenerations or dementias are poorly understood conditions. The familial forms are (1) selective thalamic degenerations and (2) thalamic degenerations associated with multiple system atrophy. Selective thalamic degenerations share clinical and pathologic features with fatal familial insomnia, an autosomal dominant disease linked to a mutation at codon 178 of the prion protein (PrP) gene that causes the substitution of asparagine for aspartic acid (178Asn mutation).