Neuroscience
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Cyclin-dependent kinase 5 (Cdk5) is a regulator of axon growth and radial neuronal migration in the developing mouse brain, and it plays critical roles in cortical structure formation and brain function. However, the function of Cdk5 in cortico-cortical and cortico-sensorimotor networks in the adult remains largely unknown. In this study, we investigated the function of Cdk5 in the rostral secondary motor cortex (M2) in the male mouse using CRISPR/Cas9 gene editing and somatic brain transgenesis, to produce M2-specific knockdown of Cdk5 in neurons in the male mouse. ⋯ Furthermore, whole-cell patch-clamp recordings in layer V green fluorescent protein (GFP)-tag pyramidal neurons revealed a decrease in the frequency and amplitude of miniature EPSCs and miniature IPSCs, as well as a reduction in the population synaptic responses (fEPSPs) in these mice. Specifically, retrograde labeling showed that Cdk5 knockdown in the M2 caused a reduction in long-range projections to the M2 from the thalamus/prefrontal cortex and claustrum. Collectively, our findings show a new regulatory role of Cdk5 in neural circuit maintenance, and that the changes in neural transmission and circuits in the mice with Cdk5 knockdown in the M2 likely contribute to the motor dysfunction in these animals.
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Excessive expression of vascular endothelial growth factor (VEGF) is a common cause of blood-brain barrier (BBB) breakdown that triggers severe complications following traumatic brain injury (TBI). It has been shown that inhibition of VEGF activities may attenuate cerebral edema in pathological conditions. Vascular endothelial growth inhibitor (VEGI; also known as TNFSF15), a cytokine produced largely by vascular endothelial cells, is capable of downregulating VEGF expression and inhibiting VEGF receptor-2 (VEGFR2) activation. ⋯ VEGI treatment resulted in a marked decrease of BBB permeability and concomitant restoration of normal ratios of VEGF/VEGI and Angpt2/Angpt1. Consistently, alleviated edema, decreased neuron cell death, and improved neurological functions were observed when the experimental animals were treated with VEGI in the early phase of TBI. Our findings suggest that administration of VEGI recombinant protein at early phases of TBI is beneficial to stabilization of the disease conditions.
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Case Reports
Damage to the Intraparietal Sulcus Impairs Magnitude Representations of Results of Complex Arithmetic Problems.
Past research investigating the role of the intraparietal sulcus (IPS) in numerical processes focused mainly on quantity and numerical comparisons as well on single digit arithmetic. The present study investigates the involvement of the IPS in estimating the results of multi-digit multiplication problems. For this purpose, the performance a 24-year-old female (JD) with brain damage in the left IPS was compared to an age-matched control group in the computation estimation task. ⋯ Most control participants used both the approximated calculation strategy that involves rounding and calculation procedures and the sense of magnitude strategy that relies on an intuitive approximated magnitude representation of the results. In contrast, JD used only the former but not the latter strategy. Together, these findings suggest that the damage to the IPS impaired JD's representations of magnitude that play an important role in this computation estimation task.
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Accumulation of amyloid-β (Aβ) in brain tissue contributes to the pathophysiology of Alzheimer's disease (AD). We recently reported that intrahippocampal transplantation of mouse bone marrow-derived microglia-like (BMDML) cells suppresses brain amyloid pathology and cognitive impairment in a mouse model of AD. How these transplanted cells interact with resident microglia remains unknown. ⋯ Brain TGF-β1 levels and resident microglial TGF-β1R expression were increased by intrahippocampal injection of BMDML cells in a mouse model of AD. Cotreatment with the TGF-βR1 inhibitor suppressed the ability of transplanted BMDML cells to increase microglial TGF-β1R expression and decrease hippocampal Aβ levels. Taken together, these findings suggested that transplanted BMDML cells secreted TGF-β1 to stimulate Aβ phagocytosis by resident microglia and decrease brain Aβ pathology.
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Mutations in γ-aminobutyric acid A receptor (GABAA) subunits and sodium channel genes, especially GABRG2 and SCN1A, have been reported to be associated with febrile seizures (FS) and genetic epilepsy with febrile seizures plus (GEFS+). GEFS+ is a well-known family of epileptic syndrome with autosomal dominant inheritance in children. Its most common phenotypes are febrile seizures often with accessory afebrile generalized tonic-clonic seizures, febrile seizures plus (FS+), severe epileptic encephalopathy, as well as other types of generalized or localization-related seizures. ⋯ In summary, mutations in the GABAA receptor can lead to a decrease in numbers of receptors, which may cause the impairment of GABAergic pathway signaling. This data has been the first time to reveal that GABRG2 mutations would affect the function of other genes, and based on this finding we hope this work would also provide a new direction for the research of GABRG2 in GEFS+. It also may provide a molecular basis for the severity of epilepsy, and guide the clinical medication for the treatment of the epilepsy focused on the function on GABAA receptors, which, might be a new strategy for genetic diagnosis and targeted treatment of epilepsy.