Pangalos, Menelas Nicolas; (1992) Biochemical approaches to the study of cortical pyramidal neurones. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The major cell type of the neocortex is the pyramidal neurone which accounts for approximately 70% of all neurones. These cells have been implicated in a number of neuropsychiatric diseases, in particular Alzheimer's disease. Markers that may identify these cells have been investigated. In ventricular cerebrospinal fluid (VCSF) no differences in amino acid or monoamine metabolite concentrations were observed in subjects with Alzheimer's disease compared to those with other neurological or psychiatric disorders. Patients with Major Depressive and Bipolar Disorders were found to have reduced 5- hydroxyindole acetic acid (5-HIAA) content compared to the other diagnostic groups, but not the concentrations of catecholamine transmitter metabolites, providing novel evidence for a serotonergic (5-HT) deficit in depression. The next phase of the research, was aimed at developing a technique to establish markers of pyramidal neurones. A subpopulation of corticofugal neocortical pyramidal neurones was destroyed following unilateral striatal injections of volkensin, a toxin which undergoes retrograde suicide transport from the site of injection. Striatal volkensin injections produced significant reductions in the number of large pyramidal neurones of the infragranular cortical layer. The selectivity of the lesion was demonstrated by the preservation of glutamic acid decarboxylase (GAD) mRNA positive cells, considered to be cortical interneurones. Ricin, another toxic lectin, but effective as a suicide transport agent only in the peripheral nervous system, produced local striatal damage but no cortical cell loss. In autoradiographic binding studies of volkensin treated animals, binding in deep neocortical layers to 5-HT1A but not 5-HT2 receptors was significantly reduced, using [3H] 8-hydroxy-2-(di-n- propylamino) tetralin (8-OH-DPAT) and [3H] ketanserin, respectively. The N-methyl-D-aspartate (NMDA) receptor complex was investigated using [3H] glutamate, [3H] glycine and the novel glycine site antagonist [3H] L-689,560. Significant reductions in binding were observed in the deep layers of volkensin treated animals using these ligands. Binding to the muscarinic M1 receptor using [3H] pirenzepine was also reduced in volkensin injected animals. The rank order of the ligands as effective markers for this subpopulation of pyramidal neurones was [3H] 8-OH-DPAT >> [3H] Pirenzepine, [3H] L-689,560 > [3H] Glutamate, [3H] Glycine > [3H] ketanserin. [3H] L-689,560 binding in total membrane preparations from Alzheimer's disease subjects was significantly reduced in the parietal and frontal but not temporal cortex when compared to controls. The findings in this thesis are thought to have advanced the understanding of the biology of pyramidal neurones and have important implications concerning the diagnosis and treatment of neuropsychiatric conditions, such as Alzheimer's disease.

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