Changes in the Excitability of Neocortical Neurons in a Mouse Model of Amyotrophic Lateral Sclerosis Are Not Specific to Corticospinal Neurons and Are Modulated by Advancing Disease

Abstract

Cell type-specific changes in neuronal excitability have been proposed to contribute to the selective degeneration of corticospinal neurons in amyotrophic lateral sclerosis (ALS) and to neocortical hyperexcitability, a prominent feature of both inherited and sporadic variants of the disease, but the mechanisms underlying selective loss of specific cell types in ALS are not known. We analyzed the physiological properties of distinct classes of cortical neurons in the motor cortex of mice of both sexes and found that they all exhibit increases in intrinsic excitability that depend on disease stage. Targeted recordings and calcium imaging further revealed that neurons adapt their functional properties to normalize cortical excitability as the disease progresses. Although different neuron classes all exhibited increases in intrinsic excitability, transcriptional profiling indicated that the molecular mechanisms underlying these changes are cell type specific. The increases in excitability in both excitatory and inhibitory cortical neurons show that selective dysfunction of neuronal cell types cannot account for the specific vulnerability of corticospinal motor neurons in ALS. Furthermore, the stage-dependent alterations in neuronal function highlight the ability of cortical circuits to adapt as disease progresses. These findings show that both disease stage and cell type must be considered when developing therapeutic strategies for treating ALS. It is not known why certain classes of neurons preferentially die in different neurodegenerative diseases. It has been proposed that the enhanced excitability of affected neurons is a major contributor to their selective loss. We show using a mouse model of amyotrophic lateral sclerosis (ALS), a disease in which corticospinal neurons exhibit selective vulnerability, that changes in excitability are not restricted to this neuronal class and that excitability does not increase monotonically with disease progression. Moreover, although all neuronal cell types tested exhibited abnormal functional properties, analysis of their gene expression demonstrated cell type-specific responses to the ALS-causing mutation. These findings suggest that therapies for ALS may need to be tailored for different cell types and stages of disease.

Motor Learning Promotes Remyelination via New and Surviving Oligodendrocytes

“…These data show a clear link between cortical myelin content, neuronal function, and motor behavior. Future work characterizing the cell-type specific changes in neuronal excitability 64 and plasticity 65 , along with circuit-level alterations in excitatory and inhibitory balance within motor cortex 66 will provide insights into the cellular and circuit origins of demyelinationinduced hyperexcitability.…”

Cytoplasmic accumulation of FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and defects in inhibitory synapses

“…Indeed, deletion of all three neurexins from PV neurons is causing a decrease in the number of synapses in this neuronal type 82 [84][85][86] . Others, however, found PV interneurons to be unaltered presymptomatically and to turn hyperexcitable during the symptomatic phase in the same SOD1 G93A mouse model 87 . In either case, those changes in PV excitability were always accompanied by hyperexcitability of layer V pyramidal neurons [84][85][86][87] .…”

“…Others, however, found PV interneurons to be unaltered presymptomatically and to turn hyperexcitable during the symptomatic phase in the same SOD1 G93A mouse model 87 . In either case, those changes in PV excitability were always accompanied by hyperexcitability of layer V pyramidal neurons [84][85][86][87] . These findings in mouse models nicely recapitulate human ALS pathology, in which cortical hyperexcitability is a frequent and, most importantly, early finding in familial and sporadic cases, including FUS mutation carriers 16,88 .…”

Early alterations of RNA metabolism and splicing from adult corticospinal neurons in an ALS mouse model

“…The mis-splicing of these transcripts, amongst others, could contribute to altered dendritic shape, synaptic transmission and intrinsic excitability of the CSN/layer V subcerebral projection neurons, which have been reported in various mouse models of the disease 14,16,17,47 , and potentially to overall motor cortex hyperexcitability, an early feature of cortical impairment in ALS patients 11 . Thus, beyond the Sod1 G86R mouse model, the data are relevant to ALS in its broad genetic heterogeneity.…”