Enriched environment ameliorates adult hippocampal neurogenesis deficits in Tcf4 haploinsufficient mice

Katharina Braun,Benjamin M Häberle,D Chichung Lie,Marie-Theres Wittmann

doi:10.1186/s12868-020-00602-3

Katharina Braun, Benjamin M Häberle + Show 2 more

Open Access

https://doi.org/10.1186/s12868-020-00602-3

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Abstract

BackgroundTranscription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellectual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 participates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life.ResultsWe here investigated whether TCF4 haploinsufficiency, which in humans causes non-syndromic forms of intellectual disability and PTHS, affects adult hippocampal neurogenesis, a process that is essential for hippocampal plasticity in rodents and potentially in humans. Young adult Tcf4 heterozygote knockout mice showed a major reduction in the level of adult hippocampal neurogenesis, which was at least in part caused by lower stem/progenitor cell numbers and impaired maturation and survival of adult-generated neurons. Interestingly, housing in an enriched environment was sufficient to enhance maturation and survival of new neurons and to substantially augment neurogenesis levels in Tcf4 heterozygote knockout mice.ConclusionThe present findings indicate that haploinsufficiency for the intellectual disability- and PTHS-linked transcription factor TCF4 not only affects embryonic neurodevelopment but impedes neurogenesis in the hippocampus of adult mice. These findings suggest that TCF4 haploinsufficiency may have a negative impact on hippocampal function throughout adulthood by impeding hippocampal neurogenesis.

Highlights

The transcription factor 4 (TCF4, Gene ID: 6925) forms together with its paralogues Transcription factor 3 (TCF3) and Transcription factor 12 (TCF12) the class I basic Helix-Loop-Helix subgroup of transcription factors [1]
Tcf4 haploinsufficiency leads to proliferation deficits in adult neurogenesis We first performed immunohistochemical analysis against Transcription factor 4 (TCF4) and select stage-specific markers to confirm the notion that TCF4 is expressed in the adult hippocampal neurogenic lineage
TCF4 co-localized with the radial glia like marker NESTIN (Fig. 1a), with MCM2, a marker for proliferating precursor cells (Fig. 1b), with DCX, a marker for immature neurons (Fig. 1c) and with CALBINDIN, a marker for mature granule cells (Fig. 1d), indicating that TCF4 is expressed during all stages of adult hippocampal neurogenesis

Summary

Introduction

The transcription factor 4 (TCF4, Gene ID: 6925) forms together with its paralogues TCF3 and TCF12 the class I basic Helix-Loop-Helix (bHLH) subgroup of transcription factors [1]. Loss of Tcf causes imbalanced generation of deep vs upper layer neurons, delays neuronal differentiation, and impairs dendritogenesis and synapse formation [14, 17, 19]. Transcription factor 4 (TCF4) has been linked to human neurodevelopmental disorders such as intellec‐ tual disability, Pitt-Hopkins Syndrome (PTHS), autism, and schizophrenia. Recent work demonstrated that TCF4 partici‐ pates in the control of a wide range of neurodevelopmental processes in mammalian nervous system development including neural precursor proliferation, timing of differentiation, migration, dendritogenesis and synapse formation. TCF4 is highly expressed in the adult hippocampal dentate gyrus – one of the few brain regions where neural stem / progenitor cells generate new functional neurons throughout life

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