Minor disturbances in central nervous system function in familial neurohypophysial diabetes insipidus

Familial neurohypophysial diabetes insipidus (FNDI) is caused by a defect in vasopressin synthesis and release as a result of a heterozygous mutation in the gene for the vasopressin prohormone. The predominant characteristic of FNDI is excessive thirst and urine production. However, vasopressin not only has peripheral endocrine effects, but also regulates numerous brain functions. We investigated whether central functions are affected in FNDI, by studying neuropsychological functioning of 23 affected members (15 males, 8 females) of a large family carrying a T/G transition mutation at nucleotide 2110 (codon 116) of the vasopressin prohormone gene (Cys116Gly). The relatively large number of family members with FNDI made it possible to compare cognitive and other CNS effects in these subjects with those of family members without FNDI. Thirty-seven adult volunteers (20 males, 17 females) from the same family and 11 non-family members (2 males, 9 females) from northern part of The Netherlands were tested. The mean age of the subjects was 35+/-12 years. Of the 63 quantified neuropsychological parameters few were statistically different between the subjects with FDNI and control subjects. Memory retrieval processes and sustained attention were worse in the subjects with FDNI. Moreover, these individuals reported significantly fewer symptoms of agoraphobia and miscellaneous symptoms, and had significantly lower scores on a scale measuring anger. The performance of FNDI subjects on an auditory verbal learning test (the 15-word test learning trial) was worse, but not significantly so, than that of the subjects without FDNI. There were subjective complaints of forgetfulness and slow recalls and those were observed in daily life by non-affected family members. These moderate differences in neuropsychological performance indicate that in human FNDI parvocellular vasopressin systems that supply the brain may be less affected or give no such serious disabilities, than the magnocellular hypothalamo-neurohypophysial system that provides vasopressin for endocrine regulation of water homeostasis.     

N alpha-acetyl-[Arg8]vasopressin antagonizes the behavioral effect of [Cyt6]vasopressin-(5-9), but not of vasopressin

It has been found recently that N alpha-acetyl-[Arg8]vasopressin (Ac-VP) is present in the brain of rats. The physiological significance of this peptide is as yet unknown. Therefore, the central nervous system effects of this peptide were investigated, namely, its effects on passive avoidance behavior, exploratory behavior and body temperature. The interaction of Ac-VP with the central nervous system effects of vasopressin (VP) was also studied. Ac-VP had a slight agonistic effect on passive avoidance behavior, i.e. it facilitated passive avoidance behavior at a dose 100 times higher than that of VP. Relatively low doses (3-10 ng) of Ac-VP attenuated passive avoidance behavior, which suggests that Ac-VP interfered with an endogenous compound involved in the control of passive avoidance responding. Ac-VP was also able, albeit in higher doses (30 ng), to competitively antagonize the effect of [Cyt6]VP-(5-9), a highly potent, putative endogenous metabolite of vasopressin in the rat brain. This antagonism could be due to an interaction of Ac-VP with sites other than the V1 vasopressin receptor. Ac-VP had no significant influence on other central nervous system effects of the hormonally active nonapeptide VP, such as exploratory behavior and body temperature. These effects were readily antagonized by the V1 vasopressin receptor antagonist d(CH2)5Tyr(Me)VP. Ac-VP may be competitive antagonist of behaviorally active vasopressin metabolite(s) in the brain.     

CNS expression pattern of Lmx1b and coexpression with ptx genes suggest functional cooperativity in the development of forebrain motor control systems

In the central nervous system, acquisition of regional specification is an important developmental process. The regional specification is reflected by restricted and overlapping expression of homeobox genes, which are regulators of this event. Here, we detail the expression pattern of Lmx1b during late embryonic brain development and show that this gene is expressed in multiple regions and diverse sets of neurons. Noteworthy, the Lmx1b expression domain is shared by Ptx2 in posterior hypothalamic regions and by Ptx3 in the dopaminergic neurons of the ventral midbrain. In addition, the mutual cofactor Ldb1 is expressed in these regions. The expression of these gene sets is maintained in the adult brain. The subthalamic nucleus, where Lmx1b is coexpressed with Ptx2, and the substantia nigra/ventral tegmental area, where Lmx1b is coexpressed with Ptx3, are both ancillary nuclei of the motor control circuitry, but use different neurotransmitters. These data point to a combinatorial gene network that allows Lmx1b to diversify its regulatory actions by cooperation with specific Ptx genes.     

Species differences in brain pre-pro-neurotensin/neuromedin N mRNA distribution: the expression pattern in mice resembles more closely that of primates than rats

We have used in situ hybridization to determine the distribution of pre-pro-neurotensin/neuromedin N (NT/N) mRNA in the brain of mice and rats. In rats and mice, expression was observed in the lateral septal nucleus, nucleus accumbens, medial preoptic area, bed nucleus of the stria terminalis, lateral hypothalamus, central amygdaloid nucleus and the subicilum. However, several differences in the NT/N mRNA distribution were observed between rats and mice in other brain areas. In mice, NT/N expression was detected in the subthalamic nucleus and geniculate nucleus, whereas expression was not observed in these brain areas in rats. Surprisingly, expression was not observed in mouse mesencephalic dopaminergic (mesDA) neurons and the CA1 area of the hippocampus, areas known to contain NT/N mRNA in the rat brain. Taken together, these results show that although the brain NT/N mRNA distribution largely overlaps in mice and rats, species differences exist in specific brain areas in rodents. Moreover, these data indicate that the distribution in mice resembles most that of primates than rats.