Raphe-striatal serotonergic system in the AS/AGU mutant rat

Abstract

The AS/AGU rat is a spontaneous recessive mutation which arose in a closed colony of Albino Swiss (AS) rats. It is characterised by disordered locomotion including a wide gait, whole body tremor and frequent falling over in continuous locomotion. It has been demonstrated that there is a substantial dysfunction of the nigro-striatal dopaminergic system which begins with a marked reduction in dopamine release in the striatum, followed by a reduction in whole tissue dopamine levels and, finally, a loss of dopaminergic cells. The mutation has recently been shown to be a stop codon in the gene responsible for the activity of protein kinase C (PKC)-gamma. Although few specific functions are known for this particular isoform (and those that are appear to cover widely disparate types of CNS activity), the PKC family in general has a role in transmitter packaging and release, as well as in ion channel modulation and receptor sensitivity. It is very likely, therefore, that the mutation will affect other transmitter systems in addition to the dopaminergic system already investigated. Furthermore, all human neurodegenerative conditions which combine disordered locomotion with basal ganglia and aminergic dysfunction have shown evidence of effects on several transmitter systems. This study was undertaken, therefore, to look at the integrity and functioning of the raphe-striatal serotonergic system in the mutant, using the parent strain as a control. This is an exciting model, since any differences found must stem directly or indirectly from a single point mutation. Initial experiments were carried out to verify a) the nature of the mutation and b) the connectivity of the dorsal and median raphe nuclei to the striatum in these strains. Immunocytochemical investigations of the AS wild-type showed positive staining for PKC-gamma in many parts of the brain, including cerebral and cerebellar cortices, striatum, substantia nigra and raphe regions; no staining could be found in the AS/AGU mutant. This confirms the identification of the gene mutation. Injections of the tracer cholera toxin-B were made into the dorsal caudate-putamen (a region of the basal ganglia found to be particularly affected in previous work on the dopaminergic system). Cells of the dorsal raphe nucleus (but not the median raphe nucleus) were found to be retrogradely labelled. Labelling occurred throughout the dorsal raphe nucleus, with peak cell numbers occurring in the centre of the rostral-caudal distribution of the nucleus. Approximately a third of the cell bodies were positively stained for CB-T. This confirms that the dorsal caudate putamen receives a strong afferent input from the dorsal raphe nucleus, but that the median raphe does not project to the striatum. (Abstract shortened by ProQuest.)