Abstract
Dysfunction of nuclear distribution element-like 1 (Ndel1) is associated with schizophrenia, a neuropsychiatric disorder characterized by cognitive impairment and with seizures as comorbidity. The levels of Ndel1 are also altered in human and models with epilepsy, a chronic condition whose hallmark feature is the occurrence of spontaneous recurrent seizures and is typically associated with comorbid conditions including learning and memory deficits, anxiety, and depression. In this study, we analyzed the behaviors of mice postnatally deficient for Ndel1 in forebrain excitatory neurons (Ndel1 CKO) that exhibit spatial learning and memory deficits, seizures, and shortened lifespan. Ndel1 CKO mice underperformed in species-specific tasks, that is, the nest building, open field, Y maze, forced swim, and dry cylinder tasks. We surveyed the expression and/or activity of a dozen molecules related to Ndel1 functions and found changes that may contribute to the abnormal behaviors. Finally, we tested the impact of Reelin glycoprotein that shows protective effects in the hippocampus of Ndel1 CKO, on the performance of the mutant animals in the nest building task. Our study highlights the importance of Ndel1 in the manifestation of species-specific animal behaviors that may be relevant to our understanding of the clinical conditions shared between neuropsychiatric disorders and epilepsy.
Highlights
Nuclear distribution element-like 1 (Ndel1) was initially characterized as a binding partner of the Lis1/Dynein motor protein complex that regulates microtubule (MT) organization and intracellular transport (Niethammer et al 2000; Sasaki et al 2000; Chansard, Hong, et al 2011a; Chansard, Wang, et al 2011b)
To determine whether these mice have deficits in nest building, a proxy of well-being and social behavior (Latham and Mason 2004; Jirkof 2014; Rock et al 2014), we moved Ndel1 conditional knockout (CKO) mice and their heterozygotes CKO (Het) and WT littermates to new cages with bedding material sparsely distributed
This phenotype displayed by the Ndel1 CKO was so robust that even blinded, we were able to predict the genotype of the mice based on the performance in this species-specific task
Summary
Nuclear distribution element-like 1 (Ndel1) was initially characterized as a binding partner of the Lis1/Dynein motor protein complex that regulates microtubule (MT) organization and intracellular transport (Niethammer et al 2000; Sasaki et al 2000; Chansard, Hong, et al 2011a; Chansard, Wang, et al 2011b). The dendritic/synaptic pathologies, neuronal dispersion, and cognitive dysfunction can be mitigated upon replenishment of the glycoprotein Reelin in the hippocampus of Ndel CKO (Jiang et al 2016; Kiroski et al 2020). Since increased dosage of Lis causes MTs fragmentation (Smith et al 2000), we reasoned that Reelin confers neuroprotection in the mutant mice via Lis1-dependent MTs stabilization. These results provide evidence that Ndel and Reelin co-operate to maintain CA1 function during postnatal life
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