Slitrk2 deficiency causes hyperactivity with altered vestibular function and serotonergic dysregulation.

SLITRK2 encodes a transmembrane protein that modulates neurite outgrowth and synaptic activities and is implicated in bipolar disorder. Here, we addressed its physiological roles in mice. In the brain, the Slitrk2 protein was strongly detected in the hippocampus, vestibulocerebellum, and precerebellar nuclei-the vestibular-cerebellar-brainstem neural network including pontine gray and tegmental reticular nucleus. Slitrk2 knockout (KO) mice exhibited increased locomotor activity in novel environments, antidepressant-like behaviors, enhanced vestibular function, and increased plasticity at mossy fiber-CA3 synapses with reduced sensitivity to serotonin. A serotonin metabolite was increased in the hippocampus and amygdala, and serotonergic neurons in the raphe nuclei were decreased in Slitrk2 KO mice. When KO mice were treated with methylphenidate, lithium, or fluoxetine, the mood stabilizer lithium showed a genotype-dependent effect. Taken together, Slitrk2 deficiency causes aberrant neural network activity, synaptic integrity, vestibular function, and serotonergic function, providing molecular-neurophysiological insight into the brain dysregulation in bipolar disorders.

Cellular-resolution gene expression profiling in the neonatal marmoset brain reveals dynamic species- and region-specific differences.

Precise spatiotemporal control of gene expression in the developing brain is critical for neural circuit formation, and comprehensive expression mapping in the developing primate brain is crucial to understand brain function in health and disease. Here, we developed an unbiased, automated, large-scale, cellular-resolution in situ hybridization (ISH)-based gene expression profiling system (GePS) and companion analysis to reveal gene expression patterns in the neonatal New World marmoset cortex, thalamus, and striatum that are distinct from those in mice. Gene-ontology analysis of marmoset-specific genes revealed associations with catalytic activity in the visual cortex and neuropsychiatric disorders in the thalamus. Cortically expressed genes with clear area boundaries were used in a three-dimensional cortical surface mapping algorithm to delineate higher-order cortical areas not evident in two-dimensional ISH data. GePS provides a powerful platform to elucidate the molecular mechanisms underlying primate neurobiology and developmental psychiatric and neurological disorders.

Response to Commentary on "The neuroinvasive potential of SARS-CoV-2 may play a role in the respiratory failure of COVID-19 patients".

In a recent review, we have suggested a neuroinvasive potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its possible role in the causation of acute respiratory failure of coronavirus disease 2019 (COVID-19) patients (J Med Viol doi: 10.1002/jmv.25728), based upon the clinical and experimental data available on the past SARS-CoV-1 and the recent SARS-CoV-2 pandemic. In this article, we provide new evidence recently reported regarding the neurotropic potential of SARS-CoV-2 and respond to several comments on our previously published article. In addition, we also discuss the peculiar manifestations of respiratory failure in COVID-19 patients and the possible involvement of nervous system.

The neuroinvasive potential of SARS-CoV2 may play a role in the respiratory failure of COVID-19 patients.

Following the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV), another highly pathogenic coronavirus named SARS-CoV-2 (previously known as 2019-nCoV) emerged in December 2019 in Wuhan, China, and rapidly spreads around the world. This virus shares highly homological sequence with SARS-CoV, and causes acute, highly lethal pneumonia coronavirus disease 2019 (COVID-19) with clinical symptoms similar to those reported for SARS-CoV and MERS-CoV. The most characteristic symptom of patients with COVID-19 is respiratory distress, and most of the patients admitted to the intensive care could not breathe spontaneously. Additionally, some patients with COVID-19 also showed neurologic signs, such as headache, nausea, and vomiting. Increasing evidence shows that coronaviruses are not always confined to the respiratory tract and that they may also invade the central nervous system inducing neurological diseases. The infection of SARS-CoV has been reported in the brains from both patients and experimental animals, where the brainstem was heavily infected. Furthermore, some coronaviruses have been demonstrated able to spread via a synapse-connected route to the medullary cardiorespiratory center from the mechanoreceptors and chemoreceptors in the lung and lower respiratory airways. Considering the high similarity between SARS-CoV and SARS-CoV2, it remains to make clear whether the potential invasion of SARS-CoV2 is partially responsible for the acute respiratory failure of patients with COVID-19. Awareness of this may have a guiding significance for the prevention and treatment of the SARS-CoV-2-induced respiratory failure.

Calcium-dependent activator protein for secretion 2 (CADPS2) deficiency causes abnormal synapse development in hippocampal mossy fiber terminals.

Hippocampal mossy fibers (MFs) project from dentate gyrus granule cells onto the CA2-CA3 region. MF-mediated synaptic transmission plays an important role in hippocampal learning and memory. However, the molecular mechanisms underlying MF synaptic development and subsequent functional organization are not fully understood. We previously reported that calcium-dependent activator protein for secretion 2 (CADPS2, also known as CAPS2) regulates the secretion of dense-core vesicles (DCVs). Because CADPS2 is strongly expressed in MF terminals, we hypothesized that CADPS2 regulates the development and functional organization of MF synapses by controlling the secretion of DCVs and their contents. To test this, we compared the synaptic microstructures of hippocampal MF terminals in Cadps2 knockout (KO) mice and wild-type (WT) mice by electron microscopy (EM). On postnatal day 15 (P15), KO mice exhibited morphological abnormalities in MF boutons, including smaller bouton size, a larger number of DCVs and a smaller number of post-synaptic densities (PSDs), compared with WT mice. In adults (P56), MF boutons were larger in KO mice. Synaptic vesicles (SVs) were increased but with a lower density compared with the WT. Furthermore, the number of SVs was decreased near the active zone. Moreover, MF-innervated CA3 postsynapses in KO mice displayed aberrant structures at the postsynaptic density (PSD), with an increased number of PSDs (likely because of a larger number of perforated PSDs), compared with WT mice. Taken together, our findings suggest that CADPS2 plays a critical role in MF synaptic development and functional organization.

The Brain/MINDS 3D digital marmoset brain atlas.

We present a new 3D digital brain atlas of the non-human primate, common marmoset monkey (Callithrix jacchus), with MRI and coregistered Nissl histology data. To the best of our knowledge this is the first comprehensive digital 3D brain atlas of the common marmoset having normalized multi-modal data, cortical and sub-cortical segmentation, and in a common file format (NIfTI). The atlas can be registered to new data, is useful for connectomics, functional studies, simulation and as a reference. The atlas was based on previously published work but we provide several critical improvements to make this release valuable for researchers. Nissl histology images were processed to remove illumination and shape artifacts and then normalized to the MRI data. Brain region segmentation is provided for both hemispheres. The data is in the NIfTI format making it easy to integrate into neuroscience pipelines, whereas the previous atlas was in an inaccessible file format. We also provide cortical, mid-cortical and white matter boundary segmentations useful for visualization and analysis.

Digital gene atlas of neonate common marmoset brain.

Interest in the common marmoset (Callithrix jacchus) as a primate model animal has grown recently, in part due to the successful demonstration of transgenic marmosets. However, there is some debate as to the suitability of marmosets, compared to more widely used animal models, such as the macaque monkey and mouse. Especially, the usage of marmoset for animal models of human cognition and mental disorders, is still yet to be fully explored. To examine the prospects of the marmoset model for neuroscience research, the Marmoset Gene Atlas (https://gene-atlas.bminds.brain.riken.jp/) provides a whole brain gene expression atlas in the common marmoset. We employ in situ hybridization (ISH) to systematically analyze gene expression in neonate marmoset brains, which allows us to compare expression with other model animals such as mouse. We anticipate that these data will provide sufficient information to develop tools that enable us to reveal marmoset brain structure, function, cellular and molecular organization for primate brain research.

The brain-specific RasGEF very-KIND is required for normal dendritic growth in cerebellar granule cells and proper motor coordination.

Very-KIND/Kndc1/KIAA1768 (v-KIND) is a brain-specific Ras guanine nucleotide exchange factor carrying two sets of the kinase non-catalytic C-lobe domain (KIND), and is predominantly expressed in cerebellar granule cells. Here, we report the impact of v-KIND deficiency on dendritic and synaptic growth in cerebellar granule cells in v-KIND knockout (KO) mice. Furthermore, we evaluate motor function in these animals. The gross anatomy of the cerebellum, including the cerebellar lobules, layered cerebellar cortex and densely-packed granule cell layer, in KO mice appeared normal, and was similar to wild-type (WT) mice. However, KO mice displayed an overgrowth of cerebellar granule cell dendrites, compared with WT mice, resulting in an increased number of dendrites, dendritic branches and terminals. Immunoreactivity for vGluT2 (a marker for excitatory presynapses of mossy fiber terminals) was increased in the cerebellar glomeruli of KO mice, compared with WT mice. The postsynaptic density around the terminals of mossy fibers was also increased in KO mice. Although there were no significant differences in locomotor ability between KO and WT animals in their home cages or in the open field, young adult KO mice had an increased grip strength and a tendency to exhibit better motor performance in balance-related tests compared with WT animals. Taken together, our results suggest that v-KIND is required for compact dendritic growth and proper excitatory synaptic connections in cerebellar granule cells, which are necessary for normal motor coordination and balance.

Mammalian-Specific Central Myelin Protein Opalin Is Redundant for Normal Myelination: Structural and Behavioral Assessments.

Opalin, a central nervous system-specific myelin protein phylogenetically unique to mammals, has been suggested to play a role in mammalian-specific myelin. To elucidate the role of Opalin in mammalian myelin, we disrupted the Opalin gene in mice and analyzed the impacts on myelination and behavior. Opalin-knockout (Opalin-/-) mice were born at a Mendelian ratio and had a normal body shape and weight. Interestingly, Opalin-/- mice had no obvious abnormalities in major myelin protein compositions, expression of oligodendrocyte lineage markers, or domain organization of myelinated axons compared with WT mice (Opalin+/+) mice. Electron microscopic observation of the optic nerves did not reveal obvious differences between Opalin+/+ and Opalin-/- mice in terms of fine structures of paranodal loops, transverse bands, and multi-lamellae of myelinated axons. Moreover, sensory reflex, circadian rhythm, and locomotor activity in the home cage, as well as depression-like behavior, in the Opalin-/- mice were indistinguishable from the Opalin+/+ mice. Nevertheless, a subtle but significant impact on exploratory activity became apparent in Opalin-/- mice exposed to a novel environment. These results suggest that Opalin is not critical for central nervous system myelination or basic sensory and motor activities under conventional breeding conditions, although it might be required for fine-tuning of exploratory behavior.