Leduc, T. | bioRxiv Science

bioRxiv2025

Sex-dependent effects of Neuroligin-2 absence on wake/sleep architecture and electrocorticographic spectral and multifractal activities

Neuroligin-2 (NLGN2) regulates GABAergic neurotransmission and is linked to neurodevelopmental disorders. The absence of NLGN2 in male mice decreases time spent in slow wave sleep and alters electrocorticographic (ECoG) activity. We tested whether NLGN2 absence also impacts wake/sleep states in females and whether sleep phenotypes associate with specific omic signatures of the cerebral cortex. Nlgn2 knockout (KO) mice and wild-type (WT) littermates were implanted with ECoG electrodes, and ECoG signals were recorded for 48 hours. Other cohorts were submitted to motor cortex sampling followed by quantifications of the transcriptome or proteome. KO mice of both sexes spent less time in slow wave and paradoxical sleep, and KO males (but not females) showed more wake and slow wave sleep episodes during the light period. Mutant animals of both sexes showed widespread differences in wake/sleep ECoG spectral activity when compared to WT mice, including a slower theta peak frequency during paradoxical sleep. The most prominent Hurst exponent was significantly increased in Nlgn2 KO animals during all states, and Hurst exponents were less dispersed during paradoxical sleep only in KO females. Less than 31% of genes with expression changed in KO versus WT mice were shared between females and males (e.g., linked to MAPK/ERK pathway, protein regulation and neurotransmission), and it was less than 15% in the case of proteins (e.g., related to calcium signaling and excitatory synapse function). Moreover, KO males showed a higher number (> 2.5 fold) of genes with expression significantly increased and decreased compared to control mice than KO females, but only KO females presented significantly lower levels of a subset of core proteins regulating synapses (e.g., SYNGAP1, HOMER1). The findings indicate that effects of NLGN2 absence on wake/sleep phenotypes and omic landscapes depend on biological sex, and could help understanding the origin of sleep disturbances in neurodevelopmental disorders.

neuroscience↗

bioRxiv2024

Electrocorticographic and Astrocytic Signatures of Stearoyl-CoA Desaturase Inhibition in the Triple Transgenic Mouse Model of Alzheimer's Disease

The symptomatology of Alzheimers disease (AD) includes cognitive deficits and sleep disturbances. Recent findings suggest the involvement of dysfunctions in lipid metabolism, such as oleic acid build-up, in the brain of AD patients and animal models. In addition, the inhibition of stearoyl-CoA desaturase (SCD), a lipid-converting enzyme, was shown to restore memory in triple transgenic (3xTg)-AD mice. In the brain, astrocytes regulate the synthesis of specific lipids. Alterations in astrocytes and their function were reported in AD patients and animal models, and astrocytes have been implicated in the regulation of sleep. However, the relationship between sleep disturbances, astrocytes and lipid metabolism remains to be explored in AD. This project thus aimed at assessing whether the inhibition of SCD restores sleep in 3xTg-AD mice, and whether this associated with modifications in astrocytic function. Wild-type (WT) and 3xTg-AD female mice (4-months old) received intracerebroventricular infusion of a SCD inhibitor (SCDi) or vehicle for 28 days, and a 24-hour electrocorticographic (ECoG) recording was conducted post-treatment. Post-mortem brain slices were stained for the astrocytic markers glial fibrillary acidic protein (GFAP) and 10-formyltetrahydrofolate dehydrogenase (ALDH1L1) to perform cell counting and/or morphological evaluation in the hippocampus, lateral hypothalamus and thalamus. The results indicate that the reduced time spent awake and increased time spent in slow wave sleep (SWS) in 3xTg-AD mice was not restored by the SCDi treatment. Similar observations were made concerning the increased number of wake and SWS bouts in 3xTg-AD mice. Rhythmic and scale-free ECoG activity were markedly altered in 3xTg-AD mice for all wake/sleep states, and SCDi significantly altered these phenotypes in a different manner in mutant mice in comparison to WT mice. GFAP- and ALDH1L1-positive cell densities were elevated in the hippocampus and lateral hypothalamus/thalamus of 3x-Tg-AD mice, respectively, and SCDi rescued the increase in the CA1 region in particular. Overall, these findings suggest that the multiple wake/sleep alterations in 3xTg-AD mice are not substantially restored by targeting lipid metabolism using SCD inhibition, at least for the targeted age window, but that this treatment can revert hippocampal changes in astrocytes. This work will benefit the understanding of the pathophysiology related to AD and associated sleep disturbances.

neuroscience↗