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Prefrontal cortex transcriptome of Arid1b heterozygote mutantation mice and drug treated-mice age of postnatal day 120

ABSTRACT: Arid1b is a chromatin remodeler implicated in neurodevelopmental disorders. Arid1b mutant mice with haploinsufficiency (Arid1b HT) displayed persistent excitatory synaptic dysfunction from juvenile to adult stage, decreased synaptic density and transmission. Moreover, they showed autistic-like behaviors in both of early and adult stages, decreased sociability in pup USV calling and adult social interaction, and adult repetitive grooming. We found that early chronic fluoxetine treatment could carry out long-lasting restoration in electrophysiological and behavioral deficits in Arid1b HT mice. Prefrontal cortex specific transcriptomic analysis with mice at postnatal day 120 which underwent chronic fluoxetine treatment from postnatal day 3 to postnatal day 21 via mammillary milk was done to investigate transcriptomic reprogramming which contributes to this restoration.

ORGANISM(S): Mus musculus

PROVIDER: GSE203343 | GEO | 2022/07/21

REPOSITORIES: GEO

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Project description:Background - One of the causal mechanisms underlying neurodevelopmental disorders (NDDs) is chromatin modification, and the genes that regulate chromatin. AT-Rich Interactive Domain 1B (ARID1B), a chromatin modifier, has been shown to be reduced in autism spectrum disorder (ASD) and to affect rare and inherited genetic variation in a broad set of NDDs. Methods - A novel preclinical mouse model of Arid1b deficiency was created and validated to characterize and define neuroanatomical, behavioural and tran¬scriptional phenotypes. Neuroanatomy was assessed ex vivo in adult animals and in vivo longitudinally from birth to adulthood. Behavioural testing was also performed throughout development and tested all aspects of motor, learning, sociability, repetitive behaviours, seizure susceptibility and general milestones delays. Results – We validated decreased Arid1b mRNA and protein in Arid1b+/- mice, with signatures of increased axonal and synaptic gene expression and decreased transcriptional regulator and RNA processing expression in adult Arid1b+/- cerebellum. During neonatal development, Arid1b+/- mice exhibited robust impairments in ultrasonic vocalizations (USVs) and metrics of developmental growth. In addition, a striking sex dependence was observed throughout development; males had an early emergence of this neuroanatomical phenotype at postnatal day 7, whereas females had a delayed emergence around postnatal day 40. Behaviourally, as adults, Arid1b+/- mice showed low motor skills in open field exploration and normal three chambered approach. Arid1b+/- mice had learning and memory deficits in novel object recognition but not in visual discrimination and reversal touchscreen tasks. Social interactions in the male-female social dyad with USVs revealed social deficits on some but not all parameters. No repetitive behaviours were observed. Brains of adult Arid1b+/- mice had a smaller cerebellum and a larger hippocampus and corpus callosum. These results stand in contrast to previously reported data highlighting losses in corpus callosum volume in mice. Limitations – The behaviour and neuroimaging analyses were done on separate cohorts of mice, which did not allow a direct correlation between the imaging and behavioural findings, and the transcriptomic analyses was exploratory, with no validation of altered expression beyond Arid1b. Conclusions – This study represents a full validation and investigation of a novel model of Arid1b+/- haploinsufficiency throughout development and highlights the importance of examining both sexes throughout development in NDDs.

Project description:Newborn neurons enter an extended maturation stage, during which they acquire excitability characteristics crucial for development of presynaptic and postsynaptic connectivity. In contrast to earlier specification programs, little is known aboutthe regulatory mechanisms that control neuronal maturation. The Pet-1 ETS (E26 transformation-specific) factor is continuously expressed in serotonin (5-HT) neurons and initially acts in postmitotic precursors to control acquisition of 5-HT transmitter identity. Using a combination of RNA sequencing, electrophysiology, and conditional targeting approaches, we determined gene expression patterns in maturing flow-sorted 5-HT neurons and the temporal requirements for Pet-1 in shaping these patterns for functional maturation of mouse 5-HT neurons. We report a profound disruption of postmitotic expression trajectories in Pet-1 / neurons, which prevented postnatal maturation of 5-HT neuron passive and active intrinsic membrane properties, G-protein signaling, and synaptic responses to glutamatergic, lysophosphatidic, and adrenergic agonists. Unexpectedly, conditional targeting revealed a postnatal stage-specific switch in Pet-1 targets from 5-HT synthesis genes to transmitter receptor genes required for afferent modulation of 5-HT neuron excitability. 5-HT1a autoreceptor expression depended transiently on Pet-1, thus revealing an early postnatal sensitive period for control of 5-HT excitability genes. Chromatin immunoprecipitation followed by sequencing revealed that Pet-1 regulates 5-HT neuron maturation through direct gene activation and repression. Moreover, Pet-1 directly regulates the 5-HT neuron maturation factor Engrailed 1, which suggests Pet-1 orchestrates maturationthrough secondary postmitotic regulatoryfactors. The early postnatal switch in Pet-1targets uncovers a distinct neonatal stage-specific function for Pet-1, during which it promotes maturation of 5-HT neuron excitability. 5-HT neuron mRNA profiles of E11.5, E15.5, and postnatal (P1-P3) wild type (WT) and Pet-1-/- mice were generated by deep sequencing, in triplicate, using Illumina HiSeq 2500. Myc-tagged Pet-1 ChIP-seq was performed on E12.5 to E14.5 hindbrains and sequencing using NextSeq 500.

Project description:Adult Neurogenesis and Gene Expression Changes in 5-HT7 Receptor Knockout Mice: In the adult, the formation of new nerve cells in the CNS is restricted to the subependymal layer and to the subgranular zone of the hippocampus (Duman et al., 2001). Clinically adult neurogenesis has received most attention for its possible role in major depression. Depressed patients have reduced hippocampal neurogenesis (Kasper & McEwen, 2008) and hippocampal volume (Colla et al., 2007). It has also been shown that chronic, but not acute, treatment with currently widely used antidepressants, most notably fluoxetine, results in increased hippocampal neurogenesis (Malberg et al., 2000; Miller et al., 2007). Pharmacologically antidepressants act by elevating the amount of synaptic serotonin (5-HT) and they do that within minutes of administration, but the clinical effect is often delayed, sometimes for weeks (Miller et al., 2007). This delay is believed to involve changes in plasticity and neurogenesis. With currently available treatment options for depression 20% or more of patients do not respond to the therapy. Thus, there is a need for an increased understanding of the mechanism behind plasticity and neurogenesis, and for the development of improved therapies for depression. We have in an ongoing project with the aim to functionally characterize the 5-HT7 receptor, one of the most recently discovered receptor subtypes for 5-HT (Lovenberg et al., 1993). Interestingly, we have found that this receptor might be a new target for the treatment of depression. Inactivation or pharmacological blockade of this receptor induces an antidepressant-like profile in several preclinical models of depression (Hedlund et al., 2005; Guscott et al., 2005; Wesolowska et al., 2006a, 2006b) and in sleep patterns (Thomas et al., 2003; Hedlund et al., 2005). Of special interest is also the finding that inhibition of the 5-HT7 receptor potentiates the effect of antidepressants in behavioral models of depression (Wesolowska et al., 2007; Bonaventure et al., 2007). We have recently determined that mice lacking lacking the 5-HT7 receptor show a 25% decrease in the number of proliferating cells in the subgranular zone of the hippocampus compared to wildtype mice. The mice were treated with BrdU, a thymidine analog that is incorporated into the DNA of cells undergoing mitosis. BrdU was then detected immunohistochemically. Both wildtype and knockout mice responded to fluoxetine treatment with an increase in the number of dividing cells. The reduction in the number of dividing cells in the 5-HT7 receptor knockout mice seemingly contradicts the antidepressant-like profile previously observed in these mice, but might on the other hand help to explain previously observed impairments in hippocampus-dependent learning seen in the knockout mice (Roberts et al., 2004) and after pharmacological blockade (Meneses, 2004). The observation that 5-HT7 receptors influence neurogenesis constitutes an entirely new regulatory mechanism for this physiologically and pathophysiologically important process. In order to further understand hippocampal neurogenesis and how it is influenced by 5-HT in general and 5-HT7 receptors in particular we propose to perform a microarray study using the glycogene array designed by the Consortium for Functional Glycomics using total RNA from the hippocampus. A comparison will be made between young adult male mice lacking the 5-HT7 receptor and wildtype sibling controls. Such a study should yield new valuable insights into the pathways regulating neurogenesis. The glycogene array is of particular interest as it includes several genes that have been shown to be either directly or indirectly involved in adult neurogenesis and to be regulated by 5-HT and antidepressants. Of particular interest are cell adhesion molecules which are glycoproteins. One such molecule is NCAM, a marker for immature neurons undergoing remodeling and plasticity (Nakagawa et al., 2002), which is upregulated by fluoxetine treatment (Varea et al., 2006). In contrast, NCAM is downregulated following 5-HT depletion (Brezun & Daszuta, 1999). Chronic fluoxetine treatment has also been shown to upregulate neuropeptide Y, Galectin I, Activin A receptor and Inhibin beta-A, all included in the glycogene array (Miller et al., 2007). Another relevant gene on the glycogene chip is ST8SiaIV (Nakagawa et al., 2002). Experimental Design: The hippocampus will be dissected and total RNA will be extracted according to recommended protocols for array studies. RNA from a sufficient number (2-3 animals) of male 5-HT7 receptor knockout mice will be pooled for each of the three replicates. Control samples will be similarly generated from wildtype siblings. The 5-HT7 receptor mice are on a genetically homogeneous background (backcrossed for 16 generation on a C57BL6/J background) so inter-animal variability should be negligible. The RNA will be analyzed on the glycogene array. 3 KO replicates + 3 WT replicates per glycogene array = 6 arrays

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Prefrontal cortex transcriptome of Arid1b heterozygote mutantation mice and drug treated-mice age of postnatal day 120

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