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

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.

Linking genetically defined neurons to behavior through a broadly applicable silencing allele.

Tools for suppressing synaptic transmission gain power when able to target highly selective neuron subtypes, thereby sharpening attainable links between neuron type, behavior, and disease; and when able to silence most any neuron subtype, thereby offering broad applicability. Here, we present such a tool, RC::PFtox, that harnesses breadth in scope along with high cell-type selection via combinatorial gene expression to deliver tetanus toxin light chain (tox), an inhibitor of vesicular neurotransmission. When applied in mice, we observed cell-type-specific disruption of vesicle exocytosis accompanied by loss of excitatory postsynaptic currents and commensurately perturbed behaviors. Among various test populations, we applied RC::PFtox to silence serotonergic neurons, en masse or a subset defined combinatorially. Of the behavioral phenotypes observed upon en masse serotonergic silencing, only one mapped to the combinatorially defined subset. These findings provide evidence for separability by genetic lineage of serotonin-modulated behaviors; collectively, these findings demonstrate broad utility of RC::PFtox for dissecting neuron functions.