Cortical interneuron-mediated inhibition delays the onset of amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis is a fatal disease resulting from motor neuron degeneration in the cortex and spinal cord. Cortical hyperexcitability is a hallmark feature of amyotrophic lateral sclerosis and is accompanied by decreased intracortical inhibition. Using electrophysiological patch-clamp recordings, we revealed parvalbumin interneurons to be hypoactive in the late pre-symptomatic SOD1*G93A mouse model of amyotrophic lateral sclerosis. We discovered that using adeno-associated virus-mediated delivery of chemogenetic technology targeted to increase the activity of the interneurons within layer 5 of the primary motor cortex, we were able to rescue intracortical inhibition and reduce pyramidal neuron hyperexcitability. Increasing the activity of interneurons in the layer 5 of the primary motor cortex was effective in delaying the onset of amyotrophic lateral sclerosis-associated motor deficits, slowing symptom progression, preserving neuronal populations, and increasing the lifespan of SOD1*G93A mice. Taken together, this study provides novel insights into the pathogenesis and treatment of amyotrophic lateral sclerosis.

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

“…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 .…”

“…Illustrating this, loss of Gabra1 77 , or of Gabra3 78 are sufficient to lead to locomotor hyperactivity and the FUS target Nrxn1, encoding a critical actor in the formation of GABAergic and glutamatergic synapses 79 , is critical in locomotor activity and social behavior in mice 80,81 . 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 .…”

Beyond the Traditional Clinical Trials for Amyotrophic Lateral Sclerosis and The Future Impact of Gene Therapy

“…The bilateral injection in the motor cortex of an AAV5 vector, increasing interneuron activity, through a chemogenetic technology, rescued inhibition of L5 neural cells. This treatment delayed neurodegeneration and motor impairment, and increased survival in SOD1-ALS mice [103]. The alteration of the interneurons activity was described not only for SOD1 mouse models, but also in TDP-43 models, and interestingly, interneurons hypoactivity is also reduced in patients with C9orf72 mutation [104,105].…”

Proteostatic imbalance and protein spreading in amyotrophic lateral sclerosis

“…Alpha MNs are critical for muscle contraction and have been, in turn, divided into (i) slow‐twitch fatigue‐resistant (SFR), (ii) fast‐twitch fatigue‐resistant (FFR), and (iii) fast‐twitch fatigable (FF). These subtypes differ in terms of metabolism and firing activity, which appear to be major determinants of MN vulnerability in ALS (Khademullah et al, 2020). ALS affects both UMNs and LMNs.…”