guanosine-triphosphate and Memory-Disorders

The present study examined muscarinic receptor/G-protein coupling in the hippocampus and the prefrontal cortex of young and aged Long-Evans rats characterized for spatial learning ability in the Morris water maze. In a highly sensitive time-resolved fluorometry GTP-Eu binding assay, muscarinic-mediated GTP-Eu binding was severely blunted in hippocampus (-32%) and prefrontal cortex (-34%) as a consequence of aging. Furthermore, the magnitude of decreased muscarinic-mediated GTP-Eu binding was significantly correlated with the severity of spatial learning impairment in hippocampus and prefrontal cortex of aged rats and was specifically decreased in the subset of aged rats that were spatial learning impaired when compared to the aged unimpaired and the young rats. Western blot data indicated a preservation of the membrane-bound M1 receptor and the Galphaq/11 protein in both brain regions. These data demonstrate that muscarinic signaling is severely impaired as a consequence of normal aging in a manner that is closely associated with age-related cognitive decline.

Topics: Age Factors; Aging; Analysis of Variance; Animals; Behavior, Animal; Cell Membrane; Dose-Response Relationship, Drug; Guanosine Triphosphate; Hippocampus; Male; Maze Learning; Memory Disorders; Muscarinic Agonists; Oxotremorine; Prefrontal Cortex; Protein Binding; Rats; Rats, Long-Evans; Receptors, Muscarinic; Space Perception

The development of the mammalian brain is dependent on extensive neuronal migration. Mutations in mice and humans that affect neuronal migration result in abnormal lamination of brain structures with associated behavioral deficits. Here, we report the identification of a hyperactive N-ethyl-N-nitrosourea (ENU)-induced mouse mutant with abnormalities in the laminar architecture of the hippocampus and cortex, accompanied by impaired neuronal migration. We show that the causative mutation lies in the guanosine triphosphate (GTP) binding pocket of alpha-1 tubulin (Tuba1) and affects tubulin heterodimer formation. Phenotypic similarity with existing mouse models of lissencephaly led us to screen a cohort of patients with developmental brain anomalies. We identified two patients with de novo mutations in TUBA3, the human homolog of Tuba1. This study demonstrates the utility of ENU mutagenesis in the mouse as a means to discover the basis of human neurodevelopmental disorders.

Topics: Amino Acid Sequence; Animals; Anxiety; Behavior, Animal; Cell Movement; Cerebral Cortex; Chromosome Mapping; Dimerization; DNA Mutational Analysis; Female; Glutamic Acid; Guanosine Triphosphate; Hippocampus; Humans; Male; Memory Disorders; Mice; Mice, Mutant Strains; Molecular Sequence Data; Mutation; Neurons; Phenotype; Serine; Tubulin