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Spinal cholinergic interneurons differentially control motoneuron excitability and alter the locomotor network operational range.

ABSTRACT: While cholinergic neuromodulation is important for locomotor circuit operation, the specific neuronal mechanisms that acetylcholine employs to regulate and fine-tune the speed of locomotion are largely unknown. Here, we show that cholinergic interneurons are present in the zebrafish spinal cord and differentially control the excitability of distinct classes of motoneurons (slow, intermediate and fast) in a muscarinic dependent manner. Moreover, we reveal that m2-type muscarinic acetylcholine receptors (mAChRs) are present in fast and intermediate motoneurons, but not in the slow motoneurons, and that their activation decreases neuronal firing. We also reveal a strong correlation between the muscarinic receptor configuration on motoneurons and the ability of the animals to locomote at different speeds, which might serve as a plasticity mechanism to alter the operational range of the locomotor networks. These unexpected findings provide new insights into the functional flexibility of motoneurons and how they execute locomotion at different speeds.

SUBMITTER: Bertuzzi M

PROVIDER: S-EPMC5792632 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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Spinal cholinergic interneurons differentially control motoneuron excitability and alter the locomotor network operational range.

Bertuzzi Maria M Ampatzis Konstantinos K

Scientific reports 20180131 1

While cholinergic neuromodulation is important for locomotor circuit operation, the specific neuronal mechanisms that acetylcholine employs to regulate and fine-tune the speed of locomotion are largely unknown. Here, we show that cholinergic interneurons are present in the zebrafish spinal cord and differentially control the excitability of distinct classes of motoneurons (slow, intermediate and fast) in a muscarinic dependent manner. Moreover, we reveal that m2-type muscarinic acetylcholine rec ...[more]

PMID: 29386582

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Project description:ObjectivePediatric obsessive-compulsive disorder (OCD) sometimes appears rapidly, even overnight, often after an infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS, describes such a situation after infection with Streptococcus pyogenes. PANDAS may result from induced autoimmunity against brain antigens, although this remains unproven. Pilot work suggests that IgG antibodies from children with PANDAS bind to cholinergic interneurons (CINs) in the striatum. CIN deficiency has been independently associated with tics in humans and with repetitive behavioral pathology in mice, making it a plausible locus of pathology. The authors sought to replicate and extend earlier work and to investigate the cellular effects of PANDAS antibodies on cholinergic interneurons.MethodsBinding of IgG to specific neurons in human and mouse brain slices was evaluated ex vivo after incubation with serum from 27 children with rigorously characterized PANDAS, both at baseline and after intravenous immunoglobulin (IVIG) treatment, and 23 matched control subjects. Binding was correlated with symptom measures. Neural activity after serum incubation was assessed in mouse slices using molecular markers and electrophysiological recording.ResultsIgG from children with PANDAS bound to CINs, but not to several other neuron types, more than IgG from control subjects, in three independent cohorts of patients. Post-IVIG serum had reduced IgG binding to CINs, and this reduction correlated with symptom improvement. Baseline PANDAS sera decreased activity of striatal CINs, but not of parvalbumin-expressing GABAergic interneurons, and altered their electrophysiological responses, in acute mouse brain slices. Post-IVIG PANDAS sera and IgG-depleted baseline sera did not alter the activity of striatal CINs.ConclusionsThese findings provide strong evidence for striatal CINs as a critical cellular target that may contribute to pathophysiology in children with rapid-onset OCD symptoms, and perhaps in other conditions.

Dataset Information

Spinal cholinergic interneurons differentially control motoneuron excitability and alter the locomotor network operational range.

Publications

Spinal cholinergic interneurons differentially control motoneuron excitability and alter the locomotor network operational range.

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