Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration.

In neurological conditions affecting the brain, early-stage neural circuit adaption is key for long-term preservation of normal behaviour. We tested if motoneurons and respective microcircuits also adapt in the initial stages of disease progression in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we found that, preceding muscle denervation and motoneuron death, recurrent inhibition mediated by Renshaw cells is reduced in half due to impaired quantal size associated with decreased glycine receptor density. Additionally, higher probability of release from proprioceptive Ia terminals leads to increased monosynaptic excitation to motoneurons. Surprisingly, the initial impairment in recurrent inhibition is not a widespread feature of inhibitory spinal circuits, such as group I inhibitory afferents, and is compensated at later stages of disease progression. We reveal that in disease conditions, spinal microcircuits undergo specific multiphasic homeostatic compensations to preserve force output.

On the origin of F-wave: involvement of central synaptic mechanisms.

Neurophysiological methods are used widely to gain information about motor neuron excitability and axon conduction in neurodegenerative diseases. The F-wave is a common biomarker used to test motor neuron properties in the diagnosis of neurological diseases. Although the origin of the F-wave is a subject of debate, the most widely accepted mechanism posits that the F-wave is generated by the backfiring of motor neurons stimulated antidromically from the periphery. In this study, we developed an ex vivo mouse sciatic nerve-attached spinal cord preparation with sensory axons severed. In this preparation, stimulation of the whole sciatic nerve or its tibial branch evoked responses with the electrophysiological signatures of F-waves. Manipulations of synaptic transmission by either removal of extracellular calcium or block of post-synaptic glutamate receptors abolished these responses. These results suggest that F-waves are mediated by spinal microcircuits activated by recurrent motor axon collaterals via glutamatergic synapses.

Pathophysiology of Dyt1-Tor1a dystonia in mice is mediated by spinal neural circuit dysfunction.

Dystonia, a neurological disorder defined by abnormal postures and disorganized movements, is considered to be a neural circuit disorder with dysfunction arising within and between multiple brain regions. Given that spinal neural circuits constitute the final pathway for motor control, we sought to determine their contribution to this movement disorder. Focusing on the most common inherited form of dystonia in humans, DYT1-TOR1A, we generated a conditional knockout of the torsin family 1 member A (Tor1a) gene in the mouse spinal cord and dorsal root ganglia (DRG). We found that these mice recapitulated the phenotype of the human condition, developing early-onset generalized torsional dystonia. Motor signs emerged early in the mouse hindlimbs before spreading caudo-rostrally to affect the pelvis, trunk, and forelimbs throughout postnatal maturation. Physiologically, these mice bore the hallmark features of dystonia, including spontaneous contractions at rest and excessive and disorganized contractions, including cocontractions of antagonist muscle groups, during voluntary movements. Spontaneous activity, disorganized motor output, and impaired monosynaptic reflexes, all signs of human dystonia, were recorded from isolated mouse spinal cords from these conditional knockout mice. All components of the monosynaptic reflex arc were affected, including motor neurons. Given that confining the Tor1a conditional knockout to DRG did not lead to early-onset dystonia, we conclude that the pathophysiological substrate of this mouse model of dystonia lies in spinal neural circuits. Together, these data provide new insights into our current understanding of dystonia pathophysiology.

Periodontal mechanoreceptors and bruxism at low bite forces.

OBJECTIVE: In this study, we examined if 6-9 Hz jaw tremor, an indirect indicator of Periodontal Mechanoreceptor (PMR) activity, is different in bruxists compared to healthy participants during production of a low-level constant bite force. METHODS: Bite force and surface EMG from the masseter muscle were recorded simultaneously as participants (13 patients, 15 controls) held a force transducer between the upper and lower incisors very gently. RESULTS: Tremor in 6-9 Hz band for bruxists was greater on average compared to controls, but the difference was not significant, both for force recordings and EMG activity. CONCLUSIONS: The low effect sizes measured with the current protocol contrast highly with those of our previous study, where larger, dynamic bite forces were used, and where jaw tremor was markedly different in bruxists compared with controls. SIGNIFICANCE: We have now gained important insight into the conditions under which abnormal jaw tremor can be elicited in bruxism. From a scientific standpoint, this is critical for understanding the 'abnormality' of PMR feedback in bruxism. From a clinical perspective, our results represent progress towards the development of an optimal protocol in which jaw tremor can serve as a biological marker of bruxism.