The events of 2020, including the pandemic which highlighted the extent of health disparities in the United States, combined with the Black Lives Matter protests, have focused public attention on the ...systemic inequities that continue to afflict our nation. Publicly available data from the National Center for Education Statistics show that our discipline of neuroscience shows the same types of disparities, particularly for African‐American students. I have drawn on data from the Integrated Postsecondary Education Data Survey of U.S. colleges and universities to show that while the number of graduates from neuroscience undergraduate and graduate degree programs has grown dramatically in this century, only a small percentage of those graduates are African American, and the numbers are growing very slowly. I also present data on the neuroscience PhD program at my institution, Delaware State University, the only Historically Black University in the United States to offer a PhD in neuroscience. Because a high percentage of our students and graduates are African American, our small, young program has the potential for great impact in diversifying our discipline of neuroscience. While elite colleges and research‐intensive universities have been engaged for decades in efforts to increase diversity in their academic programs, change is slow, and large inequities remain. With Delaware State University's neuroscience PhD program as an example, I hope to convince readers that it is time for our nation to recognize the institutions that are best positioned to serve students from communities of color, and direct resources to support their growth and success.
Activity-dependent changes in the properties of the motor system underlie the necessary adjustments in its responsiveness on the basis of the environmental and developmental demands of the organism. ...Although plastic changes in the properties of the spinal cord have historically been neglected because of the archaic belief that the spinal cord is constituted by a hardwired network that simply relays information to muscles, plenty of evidence has been accumulated showing that synapses impinging on spinal motoneurons undergo short- and long-term plasticity. In the brain, brief changes in the activity level of the network have been shown to be paralleled by changes in the intrinsic excitability of the neurons and are suggested to either reinforce or stabilize the changes at the synaptic level. However, rapid activity-dependent changes in the intrinsic properties of spinal motoneurons have never been reported. In this study, we show that in neonatal mice the intrinsic excitability of spinal motoneurons is depressed after relatively brief but sustained changes in the spinal cord network activity. Using electrophysiological techniques together with specific pharmacological blockers of KCNQ/Kv7 channels, we demonstrate their involvement in the reduction of the intrinsic excitability of spinal motoneurons. This action results from an increased M-current, the product of the activation of KCNQ/Kv7 channels, which leads to a hyperpolarization of the resting membrane potential and a decrease in the input resistance of spinal motoneurons. Computer simulations showed that specific up-regulations in KCNQ/Kv7 channels functions lead to a modulation of the intrinsic excitability of spinal motoneurons as observed experimentally. These results indicate that KCNQ/Kv7 channels play a fundamental role in the activity-dependent modulation of the excitability of spinal motoneurons.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
KCNQ/K
7 channels form a slow noninactivating K
current, also known as the M current. They activate in the subthreshold range of membrane potentials and regulate different aspects of excitability in ...neurons of the central nervous system. In spinal motoneurons (MNs), KCNQ/K
7 channels have been identified in the somata, axonal initial segment, and nodes of Ranvier, where they generate a slow, noninactivating, K
current sensitive to both muscarinic receptor-mediated inhibition and KCNQ/K
7 channel blockers. In this study, we thoroughly reevaluated the function of up- and downregulation of KCNQ/K
7 channels in mouse immature spinal MNs. Using electrophysiological techniques together with specific pharmacological modulators of the activity of KCNQ/K
7 channels, we show that enhancement of the activity of these channels decreases the excitability of spinal MNs in mouse neonates. This action on MNs results from a combination of hyperpolarization of the resting membrane potential, a decrease in the input resistance, and depolarization of the voltage threshold. On the other hand, the effect of inhibition of KCNQ/K
7 channels suggested that these channels play a limited role in regulating basal excitability. Computer simulations confirmed that pharmacological enhancement of KCNQ/K
7 channel activity decreases excitability and also suggested that the effects of inhibition of KCNQ/K
7 channels on the excitability of spinal MNs do not depend on a direct effect in these neurons but likely on spinal cord synaptic partners. These results indicate that KCNQ/K
7 channels have a fundamental role in the modulation of the excitability of spinal MNs acting both in these neurons and in their local presynaptic partners.
•Male patients with less severe SMA subtypes have higher incidence ratio and symptom vulnerability.•The SMNΔ7 mouse model does not exhibit sex differences in incidence ratio.•The SMNΔ7 mouse model ...continues to show consistency in phenotypic severity across sexes.•Sex-specific vulnerabilities in SMA patients are not present in one of the most common mouse models of SMA.
Spinal muscular atrophy (SMA) is an autosomal recessive disease that affects 1 out of every 6,000-10,000 individuals at birth, making it the leading genetic cause of infant mortality. In recent years, reports of sex differences in SMA patients have become noticeable. The SMNΔ7 mouse model is commonly used to investigate pathologies and treatments in SMA. However, studies on sex as a contributing biological variable are few and dated. Here, we rigorously investigated the effect of sex on a series of characteristics in SMA mice of the SMNΔ7 model. Incidence and lifespan of 23 mouse litters were tracked and phenotypic assessments were performed at 2-day intervals starting at postnatal day 6 for every pup until the death of the SMA pup(s) in each litter. Brain weights were also collected post-mortem. We found that male and female SMA incidence does not differ significantly, survival periods are the same across sexes, and there was no phenotypic difference between male and female SMA pups, other than for females exhibiting lesser body weights at early ages. Overall, this study ensures that sex is not a biological variable that contributes to the incidence ratio or disease severity in the SMNΔ7 mouse model.
Spinal muscular atrophy (SMA) is the leading genetic cause of death in infants. Studies with mouse models have demonstrated increased excitability and loss of afferent proprioceptive synapses on ...motor neurons (MNs). To further understand functional changes in the motor neural network occurring in SMA, we studied the intrinsic excitability and synaptic transmission of both MNs and interneurons (INs) from ventral horn in the lumbar spinal cord in the survival motor neuron (SMN)Δ7 mouse model. We found significant differences in the membrane properties of MNs in SMA mice compared to littermate controls, including hyperpolarized resting membrane potential, increased input resistance and decreased membrane capacitance. Action potential (AP) properties in MNs from SMA mice were also different from controls, including decreased rheobase current, increased amplitude and an increased afterdepolarization (ADP) potential. The relationship between AP firing frequency and injected current was reduced in MNs, as was the threshold current, while the percentage of MNs showing long-lasting potentiation (LLP) in the intrinsic excitability was higher in SMA mice. INs showed a high rate of spontaneous firing, and those from SMA mice fired at higher frequency. INs from SMA mice showed little difference in their input-output relationship, threshold current, and plasticity in intrinsic excitability. The changes observed in both passive membrane and AP properties suggest greater overall excitability in both MNs and INs in SMA mice, with MNs showing more differences. There were also changes of synaptic currents in SMA mice. The average charge transfer per post-synaptic current of spontaneous excitatory and inhibitory synaptic currents (sEPSCs/sIPSCs) were lower in SMA MNs, while in INs sIPSC frequency was higher. Strikingly in light of the known loss of excitatory synapses on MNs, there was no difference in sEPSC frequency in MNs from SMA mice compared to controls. For miniature synaptic currents, mEPSC frequency was higher in SMA MNs, while for SMA INs, both mEPSC and mIPSC frequencies were higher. In SMA-affected mice we observed alterations of intrinsic and synaptic properties in both MNs and INs in the spinal motor network that may contribute to the pathophysiology, or alternatively, may be a compensatory response to preserve network function.
Spinalmuscular atrophy (SMA) is a neuromuscular disease that affects as many as 1 in 6000 individuals at birth, making it the leading genetic cause of infant mortality. A growing number of studies ...indicate that SMA is a multi‐system disease. The cerebellum has received little attention even though it plays an important role in motor function and widespread pathology has been reported in the cerebella of SMA patients. In this study, we assessed SMA pathology in the cerebellum using structural and diffusion magnetic resonance imaging, immunohistochemistry, and electrophysiology with the SMNΔ7 mouse model. We found a significant disproportionate loss in cerebellar volume, decrease in afferent cerebellar tracts, selective lobule‐specific degeneration of Purkinje cells, abnormal lobule foliation and astrocyte integrity, and a decrease in spontaneous firing of cerebellar output neurons in the SMA mice compared to controls. Our data suggest that defects in cerebellar structure and function due to decreased survival motor neuron (SMN) levels impair the functional cerebellar output affecting motor control, and that cerebellar pathology should be addressed to achieve comprehensive treatment and therapy for SMA patients.
Our study showed structural and functional abnormalities in the cerebellum of spinal muscular atrophy (SMA) mice. SMA cerebella display lobule‐specific structural (red, darker shade = greater effect) and Purkinje cell degeneration (PC, green). Granule cell proliferation and migration through the molecular layer (ML) is abnormal in anterior and posterior lobules (blue); the tract formation of inferior and middle peduncles (pink, lighter shade = less tract formation) and functional output (purple) of deep cerebellar nuclei (DCN) neurons are decreased in SMA cerebella.
Sex is a significant risk factor in many neurodegenerative disorders. A better understanding of the molecular mechanisms behind sex differences could help develop more targeted therapies that would ...lead to better outcomes. Untreated spinal muscular atrophy (SMA) is the leading genetic motor disorder causing infant mortality. SMA has a broad spectrum of severity ranging from prenatal death to infant mortality to normal lifespan with some disability. Scattered evidence points to a sex-specific vulnerability in SMA. However, the role of sex as a risk factor in SMA pathology and treatment has received limited attention.
Systematically investigate sex differences in the incidence, symptom severity, motor function of patients with different types of SMA, and in the development of SMA1 patients.
Aggregated data of SMA patients were obtained from the TREAT-NMD Global SMA Registry and the Cure SMA membership database by data enquiries. Data were analyzed and compared with publicly available standard data and data from published literature.
The analysis of the aggregated results from the TREAT-NMD dataset revealed that the male/female ratio was correlated to the incidence and prevalence of SMA from different countries; and for SMA patients, more of their male family members were affected by SMA. However, there was no significant difference of sex ratio in the Cure SMA membership dataset. As quantified by the clinician severity scores, symptoms were more severe in males than females in SMA types 2 and 3b. Motor function scores measured higher in females than males in SMA types 1, 3a and 3b. The head circumference was more strongly affected in male SMA type 1 patients.
The data in certain registry datasets suggest that males may be more vulnerable to SMA than females. The variability observed indicates that more investigation is necessary to fully understand the role of sex differences in SMA epidemiology, and to guide development of more targeted treatments.
•Our data provide the first report of functional neuronal defects in the motor cortex and cerebellum in an SMA mouse model.•The observed differences were dependent on both brain region and ...developmental stage.•Spontaneous firing and network activity were significantly lower in the cerebellum but not in the motor cortex.•The excitability and synaptic transmission of the output neurons in both cerebellum and motor cortex were altered.•Our study suggests the impairment of motor control outputs from these two brain regions in SMA mice.
Spinal muscular atrophy (SMA) is a devastating genetic neuromuscular disease. Diffuse neuropathology has been reported in SMA patients and mouse models, however, functional changes in brain regions have not been studied. In the SMNΔ7 mouse model, we identified three types of differences in neuronal function in the cerebellum and motor cortex from two age groups: P7-9 (P7) and P11-14 (P11). Microelectrode array studies revealed significantly lower spontaneous firing and network activity in the cerebellum of SMA mice in both age groups, but it was more profound in the P11 group. In the motor cortex, however, neural activity was not different in either age group. Whole-cell patch-clamp was used to study the function of output neurons in both brain regions. In cerebellar Purkinje cells (PCs) of SMA mice, the input resistance was larger at P7, while capacitance was smaller at P11. In the motor cortex, no difference was observed in the passive membrane properties of layer V pyramidal neurons (PN5s). The action potential threshold of both types of output neurons was depolarized in the P11 group. We also observed lower spontaneous excitatory and inhibitory synaptic activity in PN5s and PCs respectively from P11 SMA mice. Overall, these differences suggest functional alterations in the neural network in these motor regions that change during development. Our results also suggest that neuronal dysfunction in these brain regions may contribute to the pathology of SMA. Comprehensive treatment strategies may consider motor regions outside of the spinal cord for better outcomes.
Magnesium isotopic compositions are reported for twenty‐four international geological reference materials including igneous, metamorphic and sedimentary rocks, as well as phlogopite and serpentine ...minerals. The long‐term reproducibility of Mg isotopic determination, based on 4‐year analyses of olivine and seawater samples, was ≤ 0.07‰ (2s) for δ26Mg and ≤ 0.05‰ (2s) for δ25Mg. Accuracy was tested by analysis of synthetic reference materials down to the quoted long‐term reproducibility. This comprehensive dataset, plus seawater data produced in the same laboratory, serves as a reference for quality assurance and inter‐laboratory comparison of high‐precision Mg isotopic data.
Les compositions isotopiques du magnésium sont fournies pour vingt‐quatre matériaux géologiques de référence internationaux, comprenant des roches ignées, métamorphiques et sédimentaires, ainsi qu'une phlogopite et des serpentines. La reproductibilité à long terme de la détermination isotopique du Mg, basée des analyses sur quatre ans d’échantillons d'olivine et d'eau de mer, était ≤ 0.07% (2s) pour δ26Mg et ≤ 0.05% (2s) pour δ25Mg. La précision a été testée par l'analyse de matériaux de référence synthétiques jusqu’à la reproductibilité à long terme indiquée. Cette base de données complète, ainsi que des données d'eau de mer produites dans le même laboratoire, servent de référence pour l'assurance qualité et la comparaison inter‐laboratoires de haute précision des données isotopiques du Mg.
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