Dataset Information

Functional Abnormalities of Cerebellum and Motor Cortex in Spinal Muscular Atrophy Mice.

ABSTRACT: 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.

SUBMITTER: Tharaneetharan A

PROVIDER: S-EPMC7771387 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Functional Abnormalities of Cerebellum and Motor Cortex in Spinal Muscular Atrophy Mice.

Tharaneetharan Arumugarajah A Cole Madison M Norman Brandon B Romero Nayeli C NC Wooltorton Julian R A JRA Harrington Melissa A MA Sun Jianli J

Neuroscience 20201117

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 ce ...[more]

PMID: 33212215

Similar Datasets

Project description:Spinal muscular atrophy (SMA) is a progressive neuromuscular disorder caused by a loss of the survival of motor neuron 1 (SMN1) gene, resulting in a loss of spinal motor neurons (MNs), leading to muscle weakness and wasting. The pathogenesis of MN loss in SMA and the selective vulnerability in different cellular populations are not fully understood. To investigate the role of spinal astrocytes in the pathogenesis of late-onset SMA, we used a mouse model in addition to in vitro approaches. Immunostaining, Western blot analysis, small interfering ribonucleic acid (siRNA) transfections, functional assays, enzyme-linked immunosorbent assay (ELISA), behavioral tests, and electrophysiological measurements were performed. Early activation of spinal astrocytes and a reduction of the excitatory amino acid transporter 1 (EAAT1) on postnatal day (P) 20 preceded the loss of spinal MNs in SMA mice occurring on P42. EAAT1 reduction resulted in elevated glutamate levels in the spinal cord of SMA mice at P20 and P42. SMA-like astrocytes generated by siRNA and an ex vivo model of glutamate excitotoxicity involving organotypic spinal cord slice cultures revealed the critical role of glutamate homeostasis in the degeneration of MNs. The pre-emptive administration of arundic acid (AA), as an inhibitor of astrocyte activation, to SMA mice prior to the loss of motor neurons (P28) resulted in elevated EAAT1 protein levels compared to vehicle-treated SMA mice and prevented the increase of glutamate in the spinal cord and the loss of spinal MNs. Furthermore, AA preserved motor functions during behavioral experiments, the electrophysiological properties, and muscle alteration of SMA mice. In a translational approach, we transfected healthy human fibroblasts with SMN1 siRNA, resulting in reduced EAAT1 expression and reduced uptake but increased glutamate release. These findings were verified by detecting elevated glutamate levels and reduced levels of EAAT1 in cerebrospinal fluid of untreated SMA type 2 and 3 patients. In addition, glutamate was elevated in serum samples, while EAAT1 was not detectable. Our data give evidence for the crucial role of spinal astrocytes in the pathogenesis of late-onset SMA, a potential driving force for MN loss by glutamate excitotoxicity caused by EAAT1 reduction as an early pathophysiological event. Furthermore, our study introduces EAAT1 as a potential therapeutic target for additional SMN-independent therapy strategies to complement SMN-enhancing drugs.

Dataset Information

Functional Abnormalities of Cerebellum and Motor Cortex in Spinal Muscular Atrophy Mice.

Publications

Functional Abnormalities of Cerebellum and Motor Cortex in Spinal Muscular Atrophy Mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets