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The development of striatal patch/matrix organization after prenatal methylazoxymethanol: a combined
1Wadsworth Center for Laboratories and Research, New York State Department of Health, Albany 12201-0509, USA.
Abstract:
The antimitotic drug methylazoxymethanol was used to destroy striatal patch neurons during their three-day-period of neurogenesis in the rat. Single or multiple injections of methylazoxymethanol were given during embryonic days 13-15, the period when patch neurons are known to undergo their final cell division. Methylazoxymethanol treatments produced a dramatic reduction in striatal volume. Immunocytochemical analysis revealed the continued presence of patches of neurons that were substance P-immunoreactive and devoid of calbindin and enkephalin immunoreactivity. Both the number of patches and relative volume occupied by patches was reduced in methylazoxymethanol-treated striata. Patch neurons could also be labelled by an intrastriatal injection of FluoroGold during the first postnatal week. The early ingrowth of nigrostriatal dopamine afferents was less noticeably patchy in the methylazoxymethanol-treated animals, in part owing to an overall increase in density. Large reductions in the number of neurons immunoreactive for choline acetyltransferase were observed, whereas NADPH diaphorase-stained neurons were not reduced unless methylazoxymethanol was given on embryonic day 15. Injections of bromo-deoxy-uridine, either during or after the 24 h that each methylazoxymethanol injection was considered to be effective, revealed that (i) some patch neurons continued to be generated in the 24-h period following methylazoxymethanol administration, and (ii) many patch neurons were generated after the effects of methylazoxymethanol had worn off. These findings demonstrate that it was impossible to completely eliminate the patches using methylazoxymethanol injections during the period of patch neurogenesis. However, methylazoxymethanol treatment during this time did produce a dramatic loss of cells and a relatively greater reduction in patch volume. Despite this disruption, the appropriate compartmentalization of neuroactive substances appeared to be maintained.
Insights
Methylazoxymethanol treatment reduced striatal volume and patch neurons during development. However, complete elimination of patch neurons was not achieved, with some neurochemical markers remaining compartmentalized.
Area of Science:
- Neuroscience
- Developmental Neuroscience
- Neurotoxicology
Background:
- Striatal patch neurons play a crucial role in motor control and reward processing.
- Understanding the developmental trajectory of striatal patch neurons is essential for deciphering their function and vulnerability to neurotoxins.
Purpose of the Study:
- To investigate the effects of methylazoxymethanol (MAM), an antimitotic drug, on the development and survival of striatal patch neurons in rats.
- To determine if MAM can completely eliminate striatal patch neurons during their critical neurogenesis period.
Main Methods:
- Administration of methylazoxymethanol (MAM) during embryonic days 13-15 in rats to target developing striatal patch neurons.
- Immunocytochemical analysis to assess the presence and distribution of specific neuronal markers (substance P, calbindin, enkephalin, choline acetyltransferase, NADPH diaphorase).
- Bromo-deoxy-uridine (BrdU) labeling to track neurogenesis during and after MAM exposure.
Main Results:
- MAM treatment caused a significant reduction in striatal volume and the number/volume of substance P-immunoreactive patches.
- While significantly reduced, striatal patch neurons were not completely eliminated, with some generated post-MAM exposure.
- Choline acetyltransferase-immunoreactive neurons were largely reduced, but NADPH diaphorase-stained neurons were less affected unless MAM was administered later.
Conclusions:
- Methylazoxymethanol administration during the critical neurogenesis period of striatal patch neurons leads to significant cell loss and reduced patch volume.
- Complete ablation of striatal patch neurons is not achievable with MAM during this developmental window.
- Despite cell loss, the compartmentalization of key neuroactive substances within the remaining striatal architecture appears to be preserved.