Elsevier

Archives of Oral Biology

Volume 74, February 2017, Pages 21-27
Archives of Oral Biology

Tooth loss early in life suppresses neurogenesis and synaptophysin expression in the hippocampus and impairs learning in mice

https://doi.org/10.1016/j.archoralbio.2016.11.005Get rights and content

Highlights

  • Effects of early toothlessness on hippocampal neurogenesis were investigated.

  • Early toothlessness induces learning deficits.

  • Early toothlessness suppresses cell proliferation and survival in the hippocampus.

  • Early toothlessness suppresses synaptophysin expression in the hippocampus.

  • Suppressed hippocampal neurogenesis leads to spatial learning deficits.

Abstract

Objective

Tooth loss induced neurological alterations through activation of a stress hormone, corticosterone. Age-related hippocampal morphological and functional changes were accelerated by early tooth loss in senescence-accelerated mouse prone 8 (SAMP8). In order to explore the mechanism underlying the impaired hippocampal function resulting from early masticatory dysfunction due to tooth loss, we investigated the effects of early tooth loss on plasma corticosterone levels, learning ability, neurogenesis, and synaptophysin expression in the hippocampus later in life of SAMP8 mice.

Design

We examined the effects of tooth loss soon after tooth eruption (1 month of age) on plasma corticosterone levels, learning ability in the Morris water maze, newborn cell proliferation, survival and differentiation in the hippocampal dentate gyrus, and synaptophysin expression in the hippocampus of aged (8 months of age) SAMP8 mice.

Results

Aged mice with early tooth loss exhibited increased plasma corticosterone levels, hippocampus-dependent learning deficits in the Morris water maze, decreased cell proliferation, and cell survival in the dentate gyrus, and suppressed synaptophysin expression in the hippocampus. Newborn cell differentiation in the hippocampal dentate gyrus, however, was not affected by early tooth loss.

Conclusion

These findings suggest that learning deficits in aged SAMP8 mice with tooth loss soon after tooth eruption are associated with suppressed neurogenesis and decreased synaptophysin expression resulting from increased plasma corticosterone levels, and that long-term tooth loss leads to impaired cognitive function in older age.

Introduction

Learning and memory critically depend on the hippocampus, a bilateral brain structure located in the temporal lobe. New cells are generated throughout life in the subgranular cell layer of the hippocampal dentate gyrus (DG) (Gage, 2002), where they mature into functional neurons with axons extending into the hippocampal CA3 region (Hastings, 1999, Stanfield and Trice, 1988). Neuronal cell proliferation, differentiation, and survival are regulated at several levels (Lee et al., 2006), and are likely related to hippocampus-mediated learning ability (Gould, Beylin, Tanapet, Reeves, & Shors, 1999). Neurogenesis in the DG decreases with aging (Gould, Reeves et al., 1999), and the age-dependent cognitive impairment is likely related to the age-related decline in neurogenesis (Bondolfi, Ermini, Long, Ingram, & Jucker, 2004). Newborn cell generation is affected by various factors, including psychologic stress and environmental complexity (Czéh et al., 2002, Torner et al., 2009; Kempermann, Brandon, & Gage, 1998; van Praag, Kempermann, & Gage, 1999). Synaptophysin is a major integral protein of the synaptic vesicle membrane that is involved in the regulation of neurotransmitter release (Bähler, Benfenati, Valtorta, & Greengard, 1990). Synaptophysin-positive synaptic boutons are a sensitive correlate of cognitive deficits (Calhoun et al., 1998). Exposure to stress leads to reduced expression of synaptophysin in the hippocampus (Thome et al., 2001).

Impaired mastication is an epidemiologic risk factor for learning and memory dysfunction, such as dementia and Alzheimer’s disease, as well as for mortality (Shimazaki et al., 2001; Shigetomi, 1998; Kondo, Niino, & Shido, 1994). Recent studies using senescence-accelerated mouse prone 8 (SAMP8) reported that tooth loss soon after tooth eruption accelerated age-related increases in plasma corticosterone levels, spatial learning deficits, neuronal loss, and increase in astroglial responsiveness in the hippocampus (Kondo et al., 2016, Kubo et al., 2010). These findings suggest that long-term tooth loss and reduced mastication impair hippocampus-related cognitive function later in adulthood. The mechanisms underlying the effect of early tooth loss on neurogenesis in the hippocampal DG, however, are not well understood.

In the present study, we examined whether tooth removal soon after tooth eruption affects cell proliferation, cell survival, and newborn cell differentiation in the DG; synaptophysin expression in the hippocampus; and learning ability in aged SAMP8 mice.

Section snippets

Animals and experimental protocol

We used male 1-month-old SAMP8 mice (n = 66) in the present study. Mice of this strain mature normally up to 6 months of age and then exhibit features of accelerated aging with a median lifespan of only 12 months compared with the 2–3 year median lifespan of the parent strains. The characteristics of the SAMP8 strain are reported elsewhere (Flood & Morley, 1998). The mice were bred under conventional conditions and then housed in plastic cages in groups of five under controlled temperature (23 ± 1 

Results

The time course of body weight changes in both control and early toothless mice is shown in Fig. 1. Body weights of the control and early tooth loss groups decreased significantly for a few days after the procedure and then returned to the pre-procedure level; thereafter, the body weight of the early tooth loss group tended to decrease compared with that of the control group, but there was no significant difference between the control and early tooth loss groups at any time during the

Discussion

The present study showed that tooth loss soon after tooth eruption resulted in increased plasma corticosterone levels, reduced cell proliferation and cell survival in the hippocampal DG, suppressed synaptophysin expression in the hippocampus, and impaired hippocampus-dependent cognition in aged SAMP8 mice. The decrease in synaptophysin expression is consistent with previous reports that removing molars in aged SAMP8 mice leads to decreased Fos induction associated with impaired water maze

Conclusion

Aged SAMP8 mice with tooth loss soon after tooth eruption exhibited suppressed cell proliferation and survival in the hippocampal DG, and synaptophysin expression in the hippocampus, with no marked changes in newborn cell differentiation of the DG. In addition, early tooth loss results in impaired learning in the Morris water maze later in life. Early tooth loss may be a risk factor for cognitive impairment later in life.

Ethical approval

This study was approved by the animal care and use ethical committee of Asahi University School of Dentistry (10-018).

Conflict of interest

No conflict of interest declared.

Acknowledgements

This work was supported in part by a Grant-in Aid Scientific Research from the Ministry of Education, Science, and Culture of Japan (KAKENHI 20592420, 21792105, 24593113), and Research Grant of Seijoh University Faculty of Rehabilitation(20130010).

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