TY  - JOUR
AU  - Ioannidis, Valentin
AU  - Pandey, Rakshita
AU  - Bauer, Helen Friedericke
AU  - Schön, Michael
AU  - Bockmann, Jürgen
AU  - Boeckers, Tobias M
AU  - Lutz, Anne-Kathrin
TI  - Disrupted extracellular matrix and cell cycle genes in autism-associated Shank3 deficiency are targeted by lithium.
JO  - Molecular psychiatry
VL  - 29
IS  - 3
SN  - 1359-4184
CY  - London
PB  - Macmillan
M1  - DZNE-2024-00739
SP  - 704 - 717
PY  - 2024
AB  - The Shank3 gene encodes the major postsynaptic scaffolding protein SHANK3. Its mutation causes a syndromic form of autism spectrum disorder (ASD): Phelan-McDermid Syndrome (PMDS). It is characterized by global developmental delay, intellectual disorders (ID), ASD behavior, affective symptoms, as well as extra-cerebral symptoms. Although Shank3 deficiency causes a variety of molecular alterations, they do not suffice to explain all clinical aspects of this heterogenic syndrome. Since global gene expression alterations in Shank3 deficiency remain inadequately studied, we explored the transcriptome in vitro in primary hippocampal cells from Shank3∆11(-/-) mice, under control and lithium (Li) treatment conditions, and confirmed the findings in vivo. The Shank3∆11(-/-) genotype affected the overall transcriptome. Remarkably, extracellular matrix (ECM) and cell cycle transcriptional programs were disrupted. Accordingly, in the hippocampi of adolescent Shank3∆11(-/-) mice we found proteins of the collagen family and core cell cycle proteins downregulated. In vitro Li treatment of Shank3∆11(-/-) cells had a rescue-like effect on the ECM and cell cycle gene sets. Reversed ECM gene sets were part of a network, regulated by common transcription factors (TF) such as cAMP responsive element binding protein 1 (CREB1) and β-Catenin (CTNNB1), which are known downstream effectors of synaptic activity and targets of Li. These TFs were less abundant and/or hypo-phosphorylated in hippocampi of Shank3∆11(-/-) mice and could be rescued with Li in vitro and in vivo. Our investigations suggest the ECM compartment and cell cycle genes as new players in the pathophysiology of Shank3 deficiency, and imply involvement of transcriptional regulators, which can be modulated by Li. This work supports Li as potential drug in the management of PMDS symptoms, where a Phase III study is ongoing.
KW  - Animals
KW  - Nerve Tissue Proteins: genetics
KW  - Nerve Tissue Proteins: metabolism
KW  - Hippocampus: metabolism
KW  - Extracellular Matrix: metabolism
KW  - Mice
KW  - Mice, Knockout
KW  - beta Catenin: metabolism
KW  - beta Catenin: genetics
KW  - Chromosome Disorders: genetics
KW  - Chromosome Disorders: metabolism
KW  - Chromosome Deletion
KW  - Cell Cycle: drug effects
KW  - Cell Cycle: genetics
KW  - Autistic Disorder: genetics
KW  - Autistic Disorder: metabolism
KW  - Chromosomes, Human, Pair 22: genetics
KW  - Cyclic AMP Response Element-Binding Protein: metabolism
KW  - Cyclic AMP Response Element-Binding Protein: genetics
KW  - Male
KW  - Transcriptome: genetics
KW  - Autism Spectrum Disorder: genetics
KW  - Autism Spectrum Disorder: metabolism
KW  - Autism Spectrum Disorder: drug therapy
KW  - Mice, Inbred C57BL
KW  - Lithium: pharmacology
KW  - Microfilament Proteins: metabolism
KW  - Microfilament Proteins: genetics
KW  - Cells, Cultured
KW  - Shank3 protein, mouse (NLM Chemicals)
KW  - Nerve Tissue Proteins (NLM Chemicals)
KW  - beta Catenin (NLM Chemicals)
KW  - Creb1 protein, mouse (NLM Chemicals)
KW  - Cyclic AMP Response Element-Binding Protein (NLM Chemicals)
KW  - CTNNB1 protein, mouse (NLM Chemicals)
KW  - Lithium (NLM Chemicals)
KW  - Microfilament Proteins (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC11153165
C6  - pmid:38123724
DO  - DOI:10.1038/s41380-023-02362-y
UR  - https://pub.dzne.de/record/270139
ER  -