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1.
J Neurosci ; 41(2): 376-389, 2021 01 13.
Article in English | MEDLINE | ID: mdl-33219005

ABSTRACT

Dysfunction of neuronal circuits is an important determinant of neurodegenerative diseases. Synaptic dysfunction, death, and intrinsic activity of neurons are thought to contribute to the demise of normal behavior in the disease state. However, the interplay between these major pathogenic events during disease progression is poorly understood. Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by a deficiency in the ubiquitously expressed protein SMN and is characterized by motor neuron death, skeletal muscle atrophy, as well as dysfunction and loss of both central and peripheral excitatory synapses. These disease hallmarks result in an overall reduction of neuronal activity in the spinal sensory-motor circuit. Here, we show that increasing neuronal activity by chronic treatment with the FDA-approved potassium channel blocker 4-aminopyridine (4-AP) improves motor behavior in both sexes of a severe mouse model of SMA. 4-AP restores neurotransmission and number of proprioceptive synapses and neuromuscular junctions (NMJs), while having no effects on motor neuron death. In addition, 4-AP treatment with pharmacological inhibition of p53-dependent motor neuron death results in additive effects, leading to full correction of sensory-motor circuit pathology and enhanced phenotypic benefit in SMA mice. Our in vivo study reveals that 4-AP-induced increase of neuronal activity restores synaptic connectivity and function in the sensory-motor circuit to improve the SMA motor phenotype.SIGNIFICANCE STATEMENT Spinal muscular atrophy (SMA) is a neurodegenerative disease, characterized by synaptic loss, motor neuron death, and reduced neuronal activity in spinal sensory-motor circuits. However, whether these are parallel or dependent events is unclear. We show here that long-term increase of neuronal activity by the FDA-approved drug 4-aminopyridine (4-AP) rescues the number and function of central and peripheral synapses in a SMA mouse model, resulting in an improvement of the sensory-motor circuit and motor behavior. Combinatorial treatment of pharmacological inhibition of p53, which is responsible for motor neuron death and 4-AP, results in additive beneficial effects on the sensory-motor circuit in SMA. Thus, neuronal activity restores synaptic connections and improves significantly the severe SMA phenotype.


Subject(s)
Movement Disorders/drug therapy , Muscular Atrophy, Spinal/drug therapy , Psychomotor Performance/drug effects , Sensation Disorders/drug therapy , 4-Aminopyridine/therapeutic use , Animals , Cell Death/drug effects , Mice , Mice, Knockout , Motor Neurons/drug effects , Movement Disorders/etiology , Movement Disorders/psychology , Muscular Atrophy, Spinal/complications , Muscular Atrophy, Spinal/psychology , Neuromuscular Junction/drug effects , Potassium Channel Blockers/therapeutic use , Proprioception/drug effects , Sensation Disorders/etiology , Sensation Disorders/psychology , Survival of Motor Neuron 1 Protein/genetics , Synapses/drug effects , Synaptic Transmission/drug effects , Tumor Suppressor Protein p53/antagonists & inhibitors
2.
Acta Neuropathol Commun ; 11(1): 53, 2023 03 30.
Article in English | MEDLINE | ID: mdl-36997967

ABSTRACT

Intercellular communication between axons and Schwann cells is critical for attaining the complex morphological steps necessary for axon maturation. In the early onset motor neuron disease spinal muscular atrophy (SMA), many motor axons are not ensheathed by Schwann cells nor grow sufficiently in radial diameter to become myelinated. These developmentally arrested motor axons are dysfunctional and vulnerable to rapid degeneration, limiting efficacy of current SMA therapeutics. We hypothesized that accelerating SMA motor axon maturation would improve their function and reduce disease features. A principle regulator of peripheral axon development is neuregulin 1 type III (NRG1-III). Expressed on axon surfaces, it interacts with Schwann cell receptors to mediate axon ensheathment and myelination. We examined NRG1 mRNA and protein expression levels in human and mouse SMA tissues and observed reduced expression in SMA spinal cord and in ventral, but not dorsal root axons. To determine the impact of neuronal NRG1-III overexpression on SMA motor axon development, we bred NRG1-III overexpressing mice to SMA∆7 mice. Neonatally, elevated NRG1-III expression increased SMA ventral root size as well as axon segregation, diameter, and myelination resulting in improved motor axon conduction velocities. NRG1-III was not able to prevent distal axonal degeneration nor improve axon electrophysiology, motor behavior, or survival of older mice. Together these findings demonstrate that early SMA motor axon developmental impairments can be ameliorated by a molecular strategy independent of SMN replacement providing hope for future SMA combinatorial therapeutic approaches.


Subject(s)
Muscular Atrophy, Spinal , Neuregulin-1 , Animals , Humans , Mice , Axons/metabolism , Motor Neurons/metabolism , Muscular Atrophy, Spinal/genetics , Muscular Atrophy, Spinal/metabolism , Myelin Sheath/metabolism , Neuregulin-1/genetics , Neuregulin-1/metabolism
3.
Front Cell Neurosci ; 16: 1038276, 2022.
Article in English | MEDLINE | ID: mdl-36419936

ABSTRACT

The activation of the p53 pathway has been associated with neuronal degeneration in different neurological disorders, including spinal muscular atrophy (SMA) where aberrant expression of p53 drives selective death of motor neurons destined to degenerate. Since direct p53 inhibition is an unsound therapeutic approach due carcinogenic effects, we investigated the expression of the cell death-associated p53 downstream targets c-fos, perp and fas in vulnerable motor neurons of SMA mice. Fluorescence in situ hybridization (FISH) of SMA motor neurons revealed c-fos RNA as a promising candidate. Accordingly, we identified p53-dependent nuclear upregulation of c-Fos protein in degenerating motor neurons from the severe SMNΔ7 and intermediate Smn2B/- SMA mouse models. Although motor neuron-specific c-fos genetic deletion in SMA mice did not improve motor neuron survival or motor behavior, p53-dependent c-Fos upregulation marks vulnerable motor neurons in different mouse models. Thus, nuclear c-Fos accumulation may serve as a readout for therapeutic approaches targeting neuronal death in SMA and possibly other p53-dependent neurodegenerative diseases.

4.
STAR Protoc ; 3(1): 101236, 2022 03 18.
Article in English | MEDLINE | ID: mdl-35300003

ABSTRACT

Loss of synapses on spinal motor neurons is a major feature of several neurodegenerative diseases; however, analyzing these premotor synapses is challenging because of their small size and high density. This protocol describes confocal and Stimulated Emission Depletion (STED) imaging of murine spinal premotor synapses and their segment-specific quantification by confocal microscopy. We detail the preparation of spinal cord segments, followed by image acquisition and analysis. This protocol enables in-depth analysis of pathological changes in spinal premotor synapses during neurodegeneration. For complete details on the use and execution of this protocol, please refer to Buettner et al. (2021).


Subject(s)
Neurodegenerative Diseases , Spinal Cord , Animals , Mice , Microscopy, Confocal , Motor Neurons , Spinal Cord/diagnostic imaging , Synapses
5.
iScience ; 24(11): 103376, 2021 Nov 19.
Article in English | MEDLINE | ID: mdl-34825141

ABSTRACT

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by reduced survival motor neuron (SMN) protein. Recently, SMN dysfunction has been linked to individual aspects of motor circuit pathology in a severe SMA mouse model. To determine whether these disease mechanisms are conserved, we directly compared the motor circuit pathology of three SMA mouse models. The severe SMNΔ7 model exhibits vast motor circuit defects, including degeneration of motor neurons, spinal excitatory synapses, and neuromuscular junctions (NMJs). In contrast, the Taiwanese model shows very mild motor neuron pathology, but early central synaptic loss. In the intermediate Smn 2B/- model, strong pathology of central excitatory synapses and NMJs precedes the late onset of p53-dependent motor neuron death. These pathological events correlate with SMN-dependent splicing dysregulation of specific mRNAs. Our study provides a knowledge base for properly tailoring future studies and identifies central excitatory synaptopathy as a key feature of motor circuit pathology in SMA.

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