5d Optical Mouse Driver [PORTABLE]
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5d Optical Mouse Driver
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Maternally inherited duplication of chromosome 15q11-q13 (Dup15q) is a pathogenic copy number variation (CNV) associated with autism spectrum disorder (ASD). Recently, paternally derived duplication has also been shown to contribute to the development of ASD. The molecular mechanism underlying paternal Dup15q remains unclear. Here, we conduct genetic and overexpression-based screening and identify Necdin (Ndn) as a driver gene for paternal Dup15q resulting in the development of ASD-like phenotypes in mice. An excess amount of Ndn results in enhanced spine formation and density as well as hyperexcitability of cortical pyramidal neurons. We generate 15q dupΔNdn mice with a normalized copy number of Ndn by excising its one copy from Dup15q mice using a CRISPR-Cas9 system. 15q dupΔNdn mice do not show ASD-like phenotypes and show dendritic spine dynamics and cortical excitatory-inhibitory balance similar to wild type animals. Our study provides an insight into the role of Ndn in paternal 15q duplication and a mouse model of paternal Dup15q syndrome.
Autism spectrum disorder (ASD) is referred to as a group of neurodevelopmental disorders. The prevalence rate of ASD is now estimated 1 in 59 according to the Centers for Disease Control1. Accumulating studies indicate that genetic components are the major contributors to the etiology of ASD, including pathogenic rare variants of a single gene or copy number variations (CNVs)2,3,4. Some CNVs, including 15q11-q13 duplication, are overlapped as shared risk factors for both ASD and schizophrenia, suggesting that the correlation between gene dosage and phenotypes is rather complex3,5. Therefore, it is crucial to identify a driver gene within CNV to understand the pathogenesis of these psychiatric disorders.
Most individuals with Dup15q syndrome have maternally derived while paternally derived duplication has been considered as non-pathogenic CNVs15,16. Therefore, it has been widely accepted that a maternally expressed gene (MEG), UBE3A, is strongly implicated as a driver gene of Dup15q syndrome16,17. This idea is supported by an animal study18. In contrast, an investigation found individuals with paternally derived duplication also met the criteria for ASD, although its penetrance was estimated at 20% and the number of cases is still small19. Thus, it remains unclear whether paternally expressed genes (PEGs) in 15q11-q13 contribute to the pathogenesis of ASD.
To address the contribution of PEGs in 15q11-q13 for ASD, we first generated a new duplication mouse having a smaller segment than that of the original 15q dup mice and conducted behavioral analyses. We then performed a screening of each PEG to evaluate which PEGs play a role in the altered spine dynamics found in paternal 15q dup mice. Finally, we conducted rescue experiments by excluding the target gene from paternal 15q dup mice.
To confirm the contribution of Ndn to dendritic spine dynamics, we visualized dendritic spines in cortical neurons of paternal 15q dupΔNdn mice by crossing with Thy1-YFP-H mice and comparing their spine turnover rate by in vivo imaging using a two-photon microscopy. The aberrant enhanced spine formation rate in paternal 15q dup mice was completely abolished in paternal 15q dupΔNdn mice and its turnover rate was equivalent to that of WT (Fig. 5d). Surprisingly, the spine elimination rate was also normalized in paternal 15q dupΔNdn mice (Fig. 5e). Cortical E/I imbalance has been frequently observed in animal models of ASD and their correction might be one of the key points in normalizing ASD-like phenotypes34,35,36. In our previous study, paternal 15q dup mice showed a decreased frequency of inhibitory synaptic input and decreased numbers of an inhibitory synaptic vesicle marker (VGAT)9. We were able to replicate the reduced VGAT density in the somatosensory cortex of paternal 15q dup mice (Fig. 5f, g). The number of VGAT-immunopositive puncta in paternal 15q dupΔNdn mice was higher than that in paternal 15q dup mice (Fig. 5g), but similar to that in WT mice. The number of excitatory synaptic marker (VGLUT) was similar among all genotypes (Fig. 5h). These data indicated Ndn has a predominant role in the proper development of cortical circuits among mouse homologous genes in 15q11-q13.
We investigated whether 15q dupΔNdn mice could be rescued from the ASD-like behaviors found in paternal 15q dup mice, such as high anxiety in a novel environment in the open field test, decreased social interaction (based on reciprocal social interaction and three-chambered social interaction tests), and impaired reversal learning8,9,13,23. The open field test showed no significant difference between WT and paternal 15q dupΔNdn mice in exploratory activity (Fig. 6a), time spent in the center area (Fig. 6b), or anxiety index, calculated by distance in the center area divided by total distance traveled (Fig. 6c). We then performed two types of social interaction tests, the reciprocal social interaction test and three-chambered social interaction test, to verify the sociability for paternal 15q dupΔNdn mice37. In the reciprocal social interaction test, the approach time did not differ between paternal 15q dupΔNdn and WT mice (Fig. 6d). Supporting this finding, paternal 15q dupΔNdn mice did not show a defect in sociability for a stranger mouse in the three-chambered test as seen in littermate WT mice (Fig. 6e, f). We also examined the effect of Ndn removal on reversal learning ability by the Barnes maze test. A probe trial after spatial learning phase revealed that time spent in the correct quadrant was significantly increased compared to other quadrants both in WT and paternal 15q dupΔNdn mice (Fig. 6g, h). Similarly, both genotype mice showed longer time spent in a new target quadrant in a probe trial after the reversal learning phase (Fig. 6i, j). These behavioral analyses indicated that an increase in Ndn expression is required for exhibiting abnormal ASD-like behaviors in paternal 15q dup mice.
In addition to impaired social interaction, ASDs are also characterized by another trait, impaired social communication. To reveal the communication alteration in paternal 15q dupΔNdn mice, we conducted ultrasonic vocalization (USV) tests under two distinct paradigms involving USVs of pups induced by maternal isolation and female-induced male USVs in a resident-intruder paradigm38. Based on our previous studies, paternal 15q dup mice emitted an increased number of USVs on postnatal day 7 and fewer calls in female-induced male USVs in the adult stage8. Both paternal 15q dup and 15q dupΔNdn pups exhibited more USVs than WT (Supplementary Fig. 8a). Moreover, paternal 15q dupΔNdn adult male mice showed fewer USVs than WT mice when exposed to an estrus female mouse (Supplementary Fig. 8b). Therefore, these data suggest that the abnormal social communication found in paternal 15q dup mice was not caused by an effect of increased expression of Ndn.
Dup15q is recognized as one of the best-known CNVs in ASD. Due to the predominant number of individuals with its maternally derived duplication, PEGs have not been well explored as an ASD risk and have not been considered pathogenic to date. However, this does not mean that PEGs in 15q11-q13 are not related to ASD. First, the general population frequency of maternal duplication is about double that of paternal duplication19. The relatively rare occurrence of paternal duplication may have resulted in their being overlooked in previous studies. Moreover, while a few reports have shown atypical duplication in ASD, these have only included the NDN, MAGEL2, and MKRN3 genes, and excluded UBE3A39,40. Therefore, we tried to address which gene is critical for developing ASD in 15q11-q13 using a model mouse.
Early studies reported that maternally derived duplication was found in autism, not paternally derived duplication15,16. Subsequent reports of human genetics and a mouse model strongly indicated that an MEG, UBE3A, has critical roles in Dup15q syndrome18,41. Nevertheless, paternal-derived duplication has also been identified in developmental disorders, albeit that the number of individuals is still limited and its penetrance is incomplete42,43,44,45. Isles et al. first investigated a relatively large cohort of 15q11-q13 interstitial duplication19, and reported that pa