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.
Highlights
These authors contributed : Manuel Winkler, Siladitta Biswas
In line with a deficit in presynaptic GABAB receptor (GBR)-mediated inhibition in PianpKO mice, we observed a significantly reduced baclofen-mediated inhibition of the miniature excitatory postsynaptic current frequency, without a change in mEPSC amplitude (Fig. 2d)
The global phenotype of PianpKO mice indicates that Pianp is primarily involved in the regulation of neuronal function and behavior as no major phenotypic or functional alterations were found in other organs beside the brain
Summary
Deficiency of the main subunits of GBRs in mice did not reveal autism-like behaviors [26], there is evidence that GABAergic signaling is functionally impaired in ASD despite normal GABA receptor availability [22, 23, 27] Such impairment may be mediated by modifications of GABA receptor interactions with associated proteins. PianpKO mice show neuroanatomical alterations including reduced thickness of the granule cell layer in the dentate gyrus (DG) and reduced numbers of Purkinje cells in the cerebellum These alterations were accompanied by a significant deficit in presynaptic GBRmediated inhibition of glutamate release, increased neuronal apoptosis, altered gene expression including reduced expression of ASD candidate gene Erdr and autism-like behavior including enhanced anxiety, spatial learning deficits, repetitive behavior and severely impaired social interactions
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