Selective Lesions

Joseph T. Coyle Division of Child Psychiatry and Departments of Neuroscience Pharmacology and Experimental Therapeutics and Psychiatry and Behavioral Sciences, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205. 

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Lee, M. G., Chrobak, J. J., Sik, A., Wiley, R. G. Buzsaki, G. (1994). Hippocampal theta activity following selective lesion of the septal cholinergic system. Neuroscience 62, 1033-47. 

Intracerebroventricular injection of kainic acid has been shown to result in a well-characterized pattern of neuronal cell damage. In the hippocampus, kainic acid causes a selective lesion of the CA3 pyramidal neurons, an area rich in KA1 and GluR6 receptors. The lesion does not compromise passing axons, which is why this type of (excitotoxic) lesion is often referred to as axon-sparing . Kainic acid injection into the hippocampus also leads to epileptiform discharges in cells normally innervated by the damaged pyramidal neurons. 

H. M. was the first human case in which specific amnesia could be linked to selective regions of the brain. Since then, many patients have been identified as having selective lesions to the temporal lobe system, especially within the hippocampus. They have exhibited amnesias similar to H. M. s. For example, amnesic patient, R. B, who had a specific lesion in the CA1 region of hippocampus, showed profound loss of ability to form new memories of people, places, and events [5]. R. B. also lost memories regarding public and personal events that he had experienced two... 

Several brain functions have been linked to specific glutamate receptor subtypes in selected brain regions. For example, glutamatergic neurons and NMDA receptors in the hippocampus are important for longterm potentiation (FTP), a crucial component in the formation of memory (Wilson and Tonegawa, 1997). Animal models with selective lesioning or strengthen-... 

Miquel M-C, Doucet E, Riad M, Adrien J, Verge D, Hamon M. Effect of the selective lesion of serotoninergic neurons on the regional distribution of 5-HT1A receptor mRNA in the rat brain. Brain Res Mol Brain Res 1992 14 357-362. 

Despite knowing the structures of all of the DNA lesions, it remains to be determined if any one lesion is more or less toxic to the cells. As discussed above, it was originally thought that DNA interstrand cross-links were the critical lesion. Once it was realized that these lesions are very rare, opinions shifted to suggest that DNA intrastrand cross-links are more cytotoxic. Unfortunately, there is no specific data that implicates either type of lesion in cytotoxicity. For some drugs like nitrosoureas, DNA repair pathways that remove only selected lesions (i.e., 0(6)-methylguanine DNA methyltransferase) have helped to define the role of a particular lesion [24], No separate pathway has been found for repair of a specific cisplatin adduct, so this approach has not been informative. A number of experiments have been performed in which specific adducts on defined DNA sequence, have been transfected into cells. This approach has shown that an adduct inhibits replication or transcription, but this does not directly address the question of mechanism of cytotoxicity. 

Galani R, Weiss I, Cassel J-C, Kelche C. 1998. Spatial memory, habituation, and reactions to spatial and nonspatial changes in rats with selective lesions of the hippocampus, the entorhinal cortex or the subiculum. Behav Brain Res 96 1-12. 

Luthman J, Bolioli B, Tsutsumi T, Verhofstad A, Jonsson G (1987) Sprouting of striatal serotonin nerve terminals following selective lesions of nigro-striatal dopamine neurons in neonatal rat. Brain Res Bull 79 269-274. 

Luthman J, Fredriksson A, Sundstrom E, Jonsson G, Archer T (1989) Selective lesion of central dopamine or noradrenaline neuron systems in the neonatal rat motor behavior and monoamine alterations at adult stage. Behav Brain Res 33 67-77. 

It appears that multiple mechanisms exist for translesion synthesis, due to the involvement of multiple bypass polymerases. In the simplest case, one polymerase inserts a nucleotide opposite the lesion, and then the same polymerase extends the synthesis from opposite the lesion. This constitutes the one-polymerase two-step mechanism (Figure 22.23). Examples of this mode of translesion synthesis include the bypass of a TT dimer by Polr and the bypass of a (-)-trans-anU-bcn/o a ]pyrene-A 2-dG by PoIk. In a more complex scheme, following nucleotide insertion opposite the lesion by one polymerase, subsequent extension synthesis is catalyzed by another polymerase. This constitutes the two-polymerase two-step mechanism (Figure 22.23). PolC is believed to be the major extension polymerase during translesion synthesis by the two-polymerase two-step mechanism. Additionally, PoIk and Polr may also catalyze extension synthesis during the bypass of some selected lesions. 

Egawa H et al. (1990) Effects of intra-arterial chemotherapy with a new lipophilic anticancer agent estradiol-chlorambucil (KM2210) dissolved in lipiodol on experimental liver tumor in rats. J Surg Oncol 44 109-114 Feldman F et al. (1975) Selective intra-arterial embolization of bone tumors A useful adjunct in the management of selected lesions. Am J Roentgenol Radium Ther Nucl Med 123 130-139... 

Ramirez JM, Schwarzacher SW, Pierrefiche O, OUvera BM, Richter DW. Selective lesioning of the cat pre-Botzinger complex in vivo eliminates breathing but not gasping. J Physiol 1998 507 895-907. 

Gabbianf G., Gregory, A. and Baic, D. (1967) Cadmium-induced selective lesions of sensory ganglia. J. Neuropath. Eyp. Neurol 26, 498—506. 

Gabbiani, G., Badonnel, M.-C., Mathewson, S.M. and Ryan, G.B. (1974) Acute cadmium intoxication. Early selective lesions of endothelial clefts. Lab. Invest. 30, 686-695. 

Based on radioligand binding of DA-agonists and antagonists, as well as effects on adenylate cyclase or endocrine functions in tissue of intact or selectively lesioned animals, several tentative schemes involving at least four DA receptor types have been proposed (Seeman 1980, Kebabian and Caine 1979, Creese et al. 1981, Schwartz et al. 1983, Sokoloff et al. 1980, Goldberg et al. 1978). 

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