Biological psychiatry global open science · 2025
Behavioral and Prefrontal Circuit Deficits in a Newly Developed Setbp1 Haploinsufficiency Mouse Model.
СтатьяНазвание и аннотация: Перевод в очереди
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Howard MacKenzie A, Geist Mendee A, Ordemann Gregory J, Kizimenko Alena, Balice Dominic M, Guillén F Isaac, Bassey Emmanuella, Lyuboslavsky Polina, Brumback Audrey C
Аннотация
BACKGROUND: SET binding protein 1 (SETBP1) regulates the cell cycle, gene transcription, and other vital intracellular processes. SETBP1 loss-of-function variants cause the neurodevelopmental disorders SETBP1-haploinsufficiency disorder and SETBP1-related disorders (SETBP1-HD and SETBP1-RD), which are characterized by attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorder (ASD), intellectual disability/developmental delay, and other neurological disabilities. Here we sought to characterize behavioral, physiological, and cell morphology phenotypes of a newly developed mouse model of SETBP1-HD.
METHODS: We used open field, 3-chamber, and Y-maze behavioral tests to measure activity, social interest, and spatial learning, respectively. We used whole-cell current clamp recordings from medial prefrontal cortex (mPFC) layer-5 extratelencephalic projection neurons in ex vivo slices to measure cell intrinsic and spike properties. We used morphological reconstruction to measure dendritic arborization in recorded neurons.
RESULTS: Setbp1 +/- mice exhibited hyperactivity, decreased social interest, and increased olfactory exploration in behavioral tests. Ex vivo electrophysiology revealed hypoexcitability in layer-5 extratelencephalic projection neurons in the mPFC. Morphological reconstruction revealed changes to the way branch points and length are distributed within the apical dendritic arbor of these prefrontal pyramidal neurons without changes in overall length or branch number.
CONCLUSIONS: These data show that Setbp1 +/- mice exhibit phenotypes parallel to the ADHD and ASD that are common in patients with SETBP1-HD. Additionally, we identified cellular changes to a key control center for attention, social behavior, and cognitive function that may elucidate the mechanism that underlies the neuropsychiatric disabilities of this disorder.
METHODS: We used open field, 3-chamber, and Y-maze behavioral tests to measure activity, social interest, and spatial learning, respectively. We used whole-cell current clamp recordings from medial prefrontal cortex (mPFC) layer-5 extratelencephalic projection neurons in ex vivo slices to measure cell intrinsic and spike properties. We used morphological reconstruction to measure dendritic arborization in recorded neurons.
RESULTS: Setbp1 +/- mice exhibited hyperactivity, decreased social interest, and increased olfactory exploration in behavioral tests. Ex vivo electrophysiology revealed hypoexcitability in layer-5 extratelencephalic projection neurons in the mPFC. Morphological reconstruction revealed changes to the way branch points and length are distributed within the apical dendritic arbor of these prefrontal pyramidal neurons without changes in overall length or branch number.
CONCLUSIONS: These data show that Setbp1 +/- mice exhibit phenotypes parallel to the ADHD and ASD that are common in patients with SETBP1-HD. Additionally, we identified cellular changes to a key control center for attention, social behavior, and cognitive function that may elucidate the mechanism that underlies the neuropsychiatric disabilities of this disorder.