A theory of hippocampal memory based on theta phase precession

 The neural dynamics of the hippocampal network for memory encoding of novel temporal sequences is proposed based on the theta rhythm modulated firing of place cells called theta phase precession. It is hypothesized that theta phase precession is generated at the entorhinal cortex by phase locking between local field theta oscillation and neural oscillators and that the hippocampal closed network with feedforward and backward projections employ theta phase precession to create selectivity in the associative connections needed for temporal sequence storage. Our analyses and computer experiments reveal that the phase precession generated by phase locking instantaneously endows stable phase relations among neural activities in the successively changing neural population. It is concluded that theta phase precession provides biologically plausible dynamics for the memory encoding of novel temporal sequences as episodic events. Received: 18 December 2002 / Accepted: 18 March 2003 / Published online: 20 May 2003 Correspondence to: Y. Yamaguchi (e-mail: yokoy@brain.riken.go.jp, Fax: +81-48-4676938) Acknowledgements. The author would like to express acknowledgement to Drs. McNaughton and Skaggs for their discussion and comment and to Dr. Amari for his continuous encouragement. Further thanks are given to Mr. Haga and Dr. Wu for their discussion and cooperation.     

Rapid determination of free D-serine with chicken D-serine dehydratase

We have developed a simple, rapid, and inexpensive method of measuring the concentration of intrinsic free D-serine in tissue samples. This method uses chicken D-serine dehydratase in an enzymatic reaction to produce pyruvate, which is detected spectrophotometrically. Pyridoxal 5'-phosphate (PLP), a cofactor of D-serine dehydratase, increased pyruvate formation by 28%. The presence of Zn(2+) or ethylenediaminetetraacetic acid (EDTA) did not have any effect on pyruvate formation under the present assay conditions. In addition, this method was not affected by the presence of a large excess of L-serine, nor by the presence of tissue extracts, and accurately determined concentrations of 2-30 μM (200 pmol-3 nmol) of D-serine. The entire assay requires only 60 min. With this method, we determined the concentration of D-serine in various silkworm tissues. The results were in agreement with high performance liquid chromatography measurements. We found high concentrations of D-serine in silkworm larvae at day 3 of the fifth instar; specifically, 509 nmol g(-1) wet tissue in the midgut, 434 nmol g(-1) in the ovary, and 353 nmol g(-1) in the testis.     

A New Mouse Allele of Glutamate Receptor Delta 2 with Cerebellar Atrophy and Progressive Ataxia

Spinocerebellar degenerations (SCDs) are a large class of sporadic or hereditary neurodegenerative disorders characterized by progressive motion defects and degenerative changes in the cerebellum and other parts of the CNS. Here we report the identification and establishment from a C57BL/6J mouse colony of a novel mouse line developing spontaneous progressive ataxia, which we refer to as ts3. Frequency of the phenotypic expression was consistent with an autosomal recessive Mendelian trait of inheritance, suggesting that a single gene mutation is responsible for the ataxic phenotype of this line. The onset of ataxia was observed at about three weeks of age, which slowly progressed until the hind limbs became entirely paralyzed in many cases. Micro-MRI study revealed significant cerebellar atrophy in all the ataxic mice, although individual variations were observed. Detailed histological analyses demonstrated significant atrophy of the anterior folia with reduced granule cells (GC) and abnormal morphology of cerebellar Purkinje cells (PC). Study by ultra-high voltage electron microscopy (UHVEM) further indicated aberrant morphology of PC dendrites and their spines, suggesting both morphological and functional abnormalities of the PC in the mutants. Immunohistochemical studies also revealed defects in parallel fiber (PF)–PC synapse formation and abnormal distal extension of climbing fibers (CF). Based on the phenotypic similarities of the ts3 mutant with other known ataxic mutants, we performed immunohistological analyses and found that expression levels of two genes and their products, glutamate receptor delta2 (grid2) and its ligand, cerebellin1 (Cbln1), are significantly reduced or undetectable. Finally, we sequenced the candidate genes and detected a large deletion in the coding region of the grid2 gene. Our present study suggests that ts3 is a new allele of the grid2 gene, which causes similar but different phenotypes as compared to other grid2 mutants.     

Prostate cancer cells and bone stromal cells mutually interact with each other through bone morphogenetic protein-mediated signals

Functional interactions between cancer cells and the bone microenvironment contribute to the development of bone metastasis. Although the bone metastasis of prostate cancer is characterized by increased ossification, the molecular mechanisms involved in this process are not fully understood. Here, the roles of bone morphogenetic proteins (BMPs) in the interactions between prostate cancer cells and bone stromal cells were investigated. In human prostate cancer LNCaP cells, BMP-4 induced the production of Sonic hedgehog (SHH) through a Smad-dependent pathway. In mouse stromal MC3T3-E1 cells, SHH up-regulated the expression of activin receptor IIB (ActR-IIB) and Smad1, which in turn enhanced BMP-responsive reporter activities in these cells. The combined stimulation with BMP-4 and SHH of MC3T3-E1 cells cooperatively induced the expression of osteoblastic markers, including alkaline phosphatase, bone sialoprotein, collagen type II α1, and osteocalcin. When MC3T3-E1 cells and LNCaP cells were co-cultured, the osteoblastic differentiation of MC3T3-E1 cells, which was induced by BMP-4, was accelerated by SHH from LNCaP cells. Furthermore, LNCaP cells and BMP-4 cooperatively induced the production of growth factors, including fibroblast growth factor (FGF)-2 and epidermal growth factor (EGF) in MC3T3-E1 cells, and these may promote the proliferation of LNCaP cells. Taken together, our findings suggest that BMPs provide favorable circumstances for the survival of prostate cancer cells and the differentiation of bone stromal cells in the bone microenvironment, possibly leading to the osteoblastic metastasis of prostate cancer.     

Synaptic Vesicle Ultrastructural Changes in the Rat Hippocampus Induced by a Combination of α-Linolenate Deficiency and a Learning Task

Abstract: Rats fed either a safflower oil (α-linolenate-deficient) or a perilla oil (α-linolenate-sufficient) diet through two generations (F1) showed significant differences in the brightness-discrimination learning task. In this task, correct responses were lever-pressing responses, which were reinforced with dietary pellets, and incorrect responses were those with no reinforcement. The inferior learning performance in the safflower oil group was caused mainly by the inferior ability to rectify the incorrect responses through the learning sessions. In the safflower oil group after the learning task, the average densities of synaptic vesicles in the terminals of the hippocampus CA1 region were decreased by nearly 30% as compared with those in the perilla oil group, and it is notable that this difference was not detected without the learning task. These results suggest that dietary oil-induced morphological changes in synapses in the hippocampus of rats are related to the differential learning performance and that the turnover rate of synaptic vesicles in the hippocampus may be an important factor affecting learning performance.