Hippocampal microglia modifications in C57Bl/6 Pahenu2 and BTBR Pahenu2 phenylketonuria (PKU) mice depend on the genetic background, irrespective of disturbed sleep patterns

Els van der Goot; Vibeke M Bruinenberg; Femke M Hormann; Ulrich L M Eisel; Francjan J van Spronsen; Eddy A Van der Zee

doi:10.1016/j.nlm.2018.05.002

Hippocampal microglia modifications in C57Bl/6 Pah^enu2 and BTBR Pah^enu2 phenylketonuria (PKU) mice depend on the genetic background, irrespective of disturbed sleep patterns

Neurobiol Learn Mem. 2019 Apr:160:139-143. doi: 10.1016/j.nlm.2018.05.002. Epub 2018 May 14.

Authors

Els van der Goot¹, Vibeke M Bruinenberg¹, Femke M Hormann¹, Ulrich L M Eisel¹, Francjan J van Spronsen², Eddy A Van der Zee³

Affiliations

¹ Groningen Institute for Evolutionary Life Sciences (GELIFES), Molecular Neurobiology, University of Groningen, Groningen, The Netherlands.
² Division of Metabolic Diseases, Beatrix Children's Hospital, University Medical Center of Groningen, University of Groningen, Groningen, The Netherlands.
³ Groningen Institute for Evolutionary Life Sciences (GELIFES), Molecular Neurobiology, University of Groningen, Groningen, The Netherlands. Electronic address: e.a.van.der.zee@rug.nl.

PMID: 29772389
DOI: 10.1016/j.nlm.2018.05.002

Abstract

Toxic levels of phenylalanine in blood and brain is a characteristic of (untreated) phenylketonuria (PKU), leading to cognitive deficits in PKU mice. In addition, our recent findings showed that PKU mice (as well as PKU patients) have a disturbed sleep/wake cycle. As a consequence, sleep loss may contribute to cognitive deficits in PKU. Sleep loss has been linked to increased activation of microglia in the hippocampus. In this study, we set out to examine morphological features of the microglia population in the hippocampus of the mouse PKU model, using both the C57Bl/6 and the BTBR strain and their wild-type controls (age 5.3 ± 0.5 months; n = 16 per group, both males and females; n = 8 each). Microglial activation is reflected by retraction and thickening of the dendritic branches and an increase in cell body size of a microglial cell. Such morphological changes of microglia were studied by way of immunohistochemical staining for Iba-1, a microglia-specific calcium binding protein. We measured the number of microglia in seven subregions of the dorsal hippocampus. The level of microglial activation was determined, based on the ratio between the soma size and total cell size (soma size plus the area covered by the dendritic branches). Results showed subtle but statistical significant activation of hippocampal microglia in the C57Bl6, but not in the BTBR, PKU mice when compared with their wild-type controls. Also the total number of microglia was higher in the C57Bl/6 PKU (compared to the wild-type) mouse, but not in the BTBR PKU mouse. It is concluded that the C57Bl/6 PKU mouse has mildly higher microglia activity, which may support rather than hamper hippocampal homeostasis. The results further indicate that high levels of phenylalanine or disturbed sleep patterns do not consequently cause hippocampal microglial activation in the PKU mouse. It is currently unknown why the two PKU mouse strains show these differences in number and activation level of their hippocampal microglia, and to what extent it influences hippocampal functioning. Further scrutinizing the role of microglia functioning in the context of PKU is therefore warranted.

Keywords: Hippocampus; Memory; Microglia; Neuroinflammation; Phenylketonuria; Sleep.

MeSH terms

Animals
Cognitive Dysfunction* / etiology
Disease Models, Animal*
Female
Hippocampus* / pathology
Male
Mice
Mice, Inbred C57BL
Microglia* / pathology
Phenylketonurias* / complications
Sleep Wake Disorders* / etiology