Weaver mutation has differential effects on the dopamine-containing innervation of the limbic and nonlimbic striatum

Abstract

Ungerstedt¹ observed that the dopamine-containing innervation of the forebrain can be divided into two parts: a nigrostriatal system, originating mainly in the pars compacta of the substantia nigra and innervating the caudoputamen; and a mesolimbic system arising mainly in the ventral tegmental area and innervating the nucleus accumbens and olfactory tubercle. This classification has since been modified and extended with the discovery of the mesocortical dopamine system^2,3. The original distinction between nigrostriatal and mesolimbic systems nevertheless was pivotal in suggesting that the basal ganglia are related to limbic as well as to sensorimotor functions, and remains of interest because dopaminergic mechanisms may be implicated not only in the aetiology of sensorimotor impairments such as those of Parkinson's disease⁴, but also in neuropsychiatric disorders such as schizophrenia^5–7. The striatal targets of the mesolimbic and nigrostriatal systems are now known to be distinct also in terms of forebrain connections, despite some overlap of fibre projections^18,19. The nucleus accumbens–olfactory tubercle region and abutting caudoputamen (together called the ‘ventral’ or ‘limbic’ striatum) are characteristically related to limbic parts of the forebrain, whereas the large remainder of the caudoputamen (the ‘dorsal’ or ‘non-limbic’ striatum) is most closely related to sensorimotor regions^19,20,34. We report here evidence that the mesolimbic and nigrostriatal systems are differentially affected in the mutant mouse weaver, and in particular that dopamine is severely depleted in the dorsal striatum of weaver but relatively spared in the ventral striatum. We conclude that dopamine-containing fibre systems innervating the limbic and non-limbic striatum can be influenced separately in genetic disease and that genetic control, whether direct or indirect, may be exerted at the single-gene level.