Exciting Complexity: The Role of Motor Circuit Elements in ALS Pathophysiology

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal disease, characterized by the degeneration of both upper and lower motor neurons. Despite decades of research, we still to date lack a cure or disease modifying treatment, emphasizing the need for a muchimproved insight into disease mechanisms and cell type vulnerability. Altered neuronal excitability is a common phenomenon reported in ALS patients, as well as in animal models of the disease, but the cellular and circuit processes involved, as well as the causal relevance of those observations to molecular alterations and final cell death, remain poorly understood. Here, we review evidence from clinical studies, cell typespecific electrophysiology, genetic manipulations and molecular characterizations in animal models and culture experiments, which argue for a causal involvement of complex alterations of structure, function and connectivity of different neuronal subtypes within the cortical and spinal cord motor circuitries. We also summarize the current knowledge regarding the detrimental role of astrocytes and reassess the frequently proposed hypothesis of glutamate-mediated excitotoxicity with respect to changes in neuronal excitability. Together, these findings suggest multifaceted cell type-, brain area-and disease stage-specific disturbances of the excitation/inhibition balance as a cardinal aspect of ALS pathophysiology.

Cytoplasmic FUS triggers early behavioral alterations linked to cortical neuronal hyperactivity and inhibitory synaptic defects

“…PV interneurons are, however, a strong candidate according to the results of our studies, but also their involvement in TDP-43 knock-in mice 65 , and in TDP-43 transgenic mice that display degeneration of hippocampal PV positive interneurons 88 . Functional impairment of PV interneurons might represent a unifying theme in ALS pathophysiology, as multiple electrophysiological studies demonstrate hypoexcitability of PV neurons in SOD1 and TDP-43 transgenic mouse models of ALS 89 – 92 . Others, however, found PV interneurons to be unaltered presymptomatically and to turn hyperexcitable during the symptomatic phase in the same SOD1 G93A mouse model 93 .…”

Absence of Subcerebral Projection Neurons Is Beneficial in a Mouse Model of Amyotrophic Lateral Sclerosis

“…It is possible that this beneficial effect arose from targeting cortical IN that modulate the excitability and activity of corticofugal neurons 41 . Given the reported alterations in excitability of cortical neuron populations in different mouse models of the disease, 8,42 comparison between silencing and genetic ablation of adult corticofugal neurons would be particularly informative to gain a better understanding of the mechanism by which these neurons might contribute to disease onset and progression. Finally, deep molecular analysis of CSN dysfunction in ALS 11 might in the future provide a better understanding of the role of the cerebral cortex and its outputs to ALS and potentially unravel new therapeutic targets.…”

Neurophysiological Mechanisms Underlying Cortical Hyper-Excitability in Amyotrophic Lateral Sclerosis: A Review

“…This relates to the neuron’s ability to produce an output or action potential (AP) by depolarizing its membrane potential to a threshold level in response to an input. This intrinsic ability of a neuron is referred to as its “intrinsic excitability” and is defined by factors including the types and number of excitatory receptors and voltage gated ion channels (e.g., Na + , K + ) present, which shapes the neuronal output [ 12 ]. Similarly, neuronal activity typically refers to the frequency of spontaneously elicited APs or post-synaptic currents, and this depends on the neuron’s intrinsic excitability, its synaptic input strength and excitation/inhibition balance, and the coordination of excitatory and inhibitory synaptic input to generate an AP.…”

“…One proposed pathogenic mechanism that culminates in the death of upper and lower MNs is glutamate-induced excitotoxicity which results from either excessive presynaptic glutamate release or defective glutamate reuptake. This depolarizes the post-synaptic neuron and increases calcium influx, thus leading to hyper-excitability [ 12 , 13 ]. Hyper-excitability is a commonly observed feature of different cell types at several locations, including LVPNs [ 14 , 15 ] brainstem motor neurons [ 16 ], spinal motor neurons [ 17 , 18 ] and skeletal muscles [ 19 ] that may contribute to pathology in ALS.…”