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Pianp deficiency links GABAB receptor signaling and hippocampal and cerebellar neuronal cell composition to autism-like behavior.

Authors
  • Winkler, Manuel1
  • Biswas, Siladitta1
  • Berger, Stefan M2
  • Küchler, Moritz3
  • Preisendörfer, Laurens3
  • Choo, Myeongjeong4
  • Früh, Simon4
  • Rem, Pascal D4
  • Enkel, Thomas2
  • Arnold, Bernd5
  • Komljenovic, Dorde6
  • Sticht, Carsten7
  • Goerdt, Sergij1, 8
  • Bettler, Bernhard4
  • von Bohlen Und Halbach, Oliver3
  • Bartsch, Dusan2
  • Géraud, Cyrill9, 10, 11
  • 1 Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany. , (Germany)
  • 2 Department of Molecular Biology, Central Institute of Mental Health and Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. , (Germany)
  • 3 Institute of Anatomy and Cell Biology, University Medicine Greifswald, Greifswald, Germany. , (Germany)
  • 4 Department of Biomedicine, Institute of Physiology, University of Basel, Basel, Switzerland. , (Switzerland)
  • 5 Division of Molecular Immunology, German Cancer Research Center (DKFZ), Heidelberg, Germany. , (Germany)
  • 6 Division of Medical Physics in Radiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. , (Germany)
  • 7 Center for Medical Research, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. , (Germany)
  • 8 European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. , (Germany)
  • 9 Department of Dermatology, Venereology, and Allergology, University Medical Center and Medical Faculty Mannheim, Heidelberg University, and Center of Excellence in Dermatology, Mannheim, Germany. [email protected] , (Germany)
  • 10 European Center for Angioscience, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. [email protected] , (Germany)
  • 11 Section of Clinical and Molecular Dermatology, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany. [email protected] , (Germany)
Type
Published Article
Journal
Molecular psychiatry
Publication Date
Nov 01, 2020
Volume
25
Issue
11
Pages
2979–2993
Identifiers
DOI: 10.1038/s41380-019-0519-9
PMID: 31511635
Source
Medline
Language
English
License
Unknown

Abstract

Pianp (also known as Leda-1) is a type I transmembrane protein with preferential expression in the mammalian CNS. Its processing is characterized by proteolytic cleavage by a range of proteases including Adam10, Adam17, MMPs, and the γ-secretase complex. Pianp can interact with Pilrα and the GB1a subunit of the GABAB receptor (GBR) complex. A recent case description of a boy with global developmental delay and homozygous nonsense variant in PIANP supports the hypothesis that PIANP is involved in the control of behavioral traits in mammals. To investigate the physiological functions of Pianp, constitutive, global knockout mice were generated and comprehensively analyzed. Broad assessment did not indicate malformation or malfunction of internal organs. In the brain, however, decreased sizes and altered cellular compositions of the dentate gyrus as well as the cerebellum, including a lower number of cerebellar Purkinje cells, were identified. Functionally, loss of Pianp led to impaired presynaptic GBR-mediated inhibition of glutamate release and altered gene expression in the cortex, hippocampus, amygdala, and hypothalamus including downregulation of Erdr1, a gene linked to autism-like behavior. Behavioral phenotyping revealed that Pianp deficiency leads to context-dependent enhanced anxiety and spatial learning deficits, an altered stress response, severely impaired social interaction, and enhanced repetitive behavior, which all represent characteristic features of an autism spectrum disorder-like phenotype. Altogether, Pianp represents a novel candidate gene involved in autism-like behavior, cerebellar and hippocampal pathology, and GBR signaling.

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