Biology subjects

Tohyama, K.

Publications and source records attributed to Tohyama, K..

3 recordsLinked to original sources

bioRxiv2026

Intact learning and memory in mice incapable of de novo myelination

Motor skill learning stimulates and requires generation of oligodendrocytes (OLs) from their precursors (OLPs) in the adult mouse brain, but the functional role(s) of the newly formed OLs is not known. We asked whether new compact myelin sheaths are required, by genetic block of myelin basic protein (MBP) synthesis in adult OLPs and their newly-differentiating OL progeny, using tamoxifen-inducible Cre-lox recombination. Newly-differentiating OLs in these Mbp-cKO mice are unable to assemble compact myelin or normal nodes of Ranvier. Despite this, Mbp-cKOs learned a motor skill just as well as their wild type littermates. They also demonstrated normal contextual fear conditioning. Therefore, neither motor nor fear learning depends on rapid saltatory conduction in newly-myelinated circuits. Mbp-cKOs also formed normal long-term motor and contextual fear memories. Moreover, OL lineage-specific knockout of Monocarboxylate transporter-1 (Mct1), believed to be responsible for transferring metabolic substrates from OLs into axons, did not affect learning or memory consolidation. Myelin regulatory factor (Myrf)-cKOs, in which newly-differentiating OLs die and are rapidly eliminated, confirmed that newly formed OLs are required for learning and memory. Together, the data suggest that learning and memory depends on a non-canonical property of pre-myelinating or myelinating OLs, distinct from myelins cardinal role in speeding action potentials.

neuroscience↗

bioRxiv2025

A mouse model of PTEN Hamartoma Tumour Syndrome reveals that loss of the nuclear function of PTEN drives macrocephaly, lymphoid overgrowth, and late-onset cancer

PTEN Hamartoma Tumour Syndrome (PHTS) is a rare disorder characterized by germline heterozygous mutations in the PTEN tumour suppressor gene, leading to multi-organ/tissue overgrowth, autism spectrum disorder and increased cancer risk. PHTS individuals display heterogeneity in phenotypes, which has been linked in part to the diverse genetic alterations in the PTEN gene and the multifaceted functions of this protein. Indeed, while PTEN primarily functions as a PIP3 lipid phosphatase in the cytosol, regulating PI3K/AKT signalling, a pathway commonly deregulated in cancer, it also plays crucial roles in maintaining chromosomal stability through nuclear activities such as double strand (ds) DNA damage repair. Recent studies have identified a subset of missense PHTS variants that cause nuclear exclusion of PTEN, impairing its nuclear functions. Here, we present our findings from one such pathogenic variant, PTEN-R173C, frequently found in PHTS and somatic cancers. Using cell biological and mouse modelling approaches, we show that PTEN-R173C has higher PIP3 phosphatase activity than wild-type PTEN, resulting in effective regulation of canonical PI3K/AKT signalling. However, PTEN-R173C is unstable and excluded from the nucleus. Aligning with their near normal PI3K/AKT signalling, Pten+/R173Cmice display a low incidence of solid tumours compared to Pten+/-mice. Pten+/R173C mice also exhibit lymphoid hyperplasia and macrocephaly which correlates with compromised nuclear functions of PTEN-R173C. That nuclear functions are compromised is demonstrated by reduced dsDNA damage repair in Pten+/R173Cmice. Integrating PHTS patient data with findings from our mouse model, our study indicates that nuclear dysfunction of pathogenic PTEN variants is a key factor in predicting the onset of the different PHTS-associated phenotypes. We speculate that late-onset cancer in individuals with nuclear-excluded PTEN results from genetic alterations unrelated to PTEN itself, facilitated by impaired PTEN-mediated dsDNA damage repair.

genetics↗

bioRxiv2023

Oligodendrocyte dynamics dictate individual performance outcomes of working memory training in mice

Motor skill learning stimulates and requires generation of myelinating oligodendrocytes (OLs) from their precursors (OLPs). We asked whether OL production is also required for non-motor learning and cognition, using T-maze and radial arm maze tasks that tax spatial working memory. Maze training stimulated OL production in the medial prefrontal cortex (mPFC), anterior corpus callosum (genu), dorsal thalamus and hippocampal formation; myelin sheath formation was also stimulated in the genu. Genetic blockade of OL differentiation and neo-myelination in Myrf conditional-knockout mice strongly impaired training-induced improvements in maze performance. Remarkably, there was a strong positive correlation between working memory performance of individual mice and the scale of OLP proliferation and OL generation during training, but not with the number or intensity of c-Fos+ neurons in the mPFC, underscoring the key role of OL lineage cells in cognitive performance.

neuroscience↗