Chessell, Iain Patrick; (1994) Biochemical and anatomical correlates of cortical pyramidal neurones- Implications for the treatment of Alzheimer's disease. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Dysfunction of the major cell type of the neocortex, the pyramidal neurone, has been implicated in several neuropsychiatric diseases, in particular Alzheimer's Disease. Markers that identify these cells are proposed to provide essential information to enable effective pharmacological targeting of intervention in the treatment of this disease. The action of a putative partial agonist, D-cycloserine, at the glycine modulatory site of the N-methyl-D-aspartate receptor-ionophore complex (NMDA receptor), known to be present on pyramidal neurones was investigated. In membranes prepared from Alzheimer's brains, D-cycloserine was determined to have partial agonist characteristics consistent with those described in animal studies. Three lesioning paradigms using the retrogradely transported toxin, volkensin, with appropriate controls, were developed to destroy subpopulations of hippocampal CA3, corticofugal and corticocortical projecting neurones. In each case volkensin injection into the appropriate area produced losses of distant neurones, with preservation of interneurones. Biochemical sequelae following such losses were investigated using the technique of autoradiography. Unilateral entorhinal injection of volkensin produced significant loss of anterior CA3 hippocampal pyramidal neurones, sparing CA1 and the dentate gyrus. The area of ligand binding to the muscarinic M1 receptor was reduced to a greater extent than the observed neuronal loss, while binding NMDA, kainate and 5-HT1A receptors was reduced in parallel with the neuronal loss. The rank order of the receptors as effective markers of this subpopulation of pyramidal neurones was M1 > NMDA, kainate > 5-HT1A > GABAA. Unilateral intrastriatal injection of volkensin produced significant reductions in the number and size of infragranular pyramidal neurones. In autoradiographic binding studies, significant reductions in ligand binding in deep neocortical layers to the 5-HT1A, muscarinic M1, nicotinic, adenosine A1 and kainate receptors were observed compared to control, with sparing of GABAA and increases in α1 total and the 1b subtype. The rank order of receptors as effective markers of this subpopulation of pyramidal neurones was nicotinic, 5-HT1A > > kainate. M1 > adenosine A1 > GABAA, α1total, α1b. Cortical injection of volkensin produced significant reductions in the number of both infragranular and supragranular contralateral pyramidal neurones. Autoradiographic investigation of volkensin injected animals revealed significant reductions in binding to M1 and nicotinic receptors but not adenosine A1, 5-HT1A or 5-HT2 compared to ricin and control animals. These findings are thought to advance the understanding of the biology of pyramidal neurones, and have important implications concerning the treatment of Alzheimer's Disease in the context of symptomatic treatment by correction of hypoactivity of glutamatergic pyramidal neurones; and treatment of the disease progression by influencing production of amyloid, implicated in the formation of senile plaques.

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