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Early dysregulation of trigeminal motor pool excitability in a mouse model for neurodegenerative motoneuron disease
BMC Neuroscience volume 16, Article number: P31 (2015)
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative motoneuron (MN) where in fast fatigable motor units (MUs) of vulnerable motor pools preferentially degenerate followed by fast fatigue resistant and slow MUs . Excitability is a key endogenous mechanism of MN neuroprotection  and therefore we hypothesize that pre-symptomatic excitability indicates impending disease development. Using a transgenic mouse model for ALS, we performed in vitro patch-clamp electrophysiology in ALS-vulnerable trigeminal motoneurons (TMNs) retrogradely labeled from jaw closer muscles at P8-12. We proposed a novel k-means clustering approach to classify TMNs into putative fast fatigable (PFF), fast fatigue resistant (PFR) and slow (PS) MUs based on rheobase and input resistance. Interestingly, hyper-excitability was noted in PFF and PFR TMNs (Fig. 1B) while hypo-excitability was evident in a subset of PS TMNs with linear frequency-current (F-I) characteristics compared to wild-type TMNs . The F-I relationships displayed dysregulation across the motor pool (Fig. 1C). A jaw closer motor pool model was developed and simulated in MATLAB™ using observed alterations in membrane properties amongst the mutant MU types. Model results predict resistance in muscle force initiation and reduced motor pool dynamic range due to opposite changes in excitability between slow and fast TMNs (Fig. 1D).
Saxena S, Roselli F, Singh K, Leptien K, Julien JP, Gros-Louis F, et al: Neuroprotection through excitability and mTOR required in ALS motoneurons to delay disease and extend survival. Neuron. 2013, 80 (1): 80-96.
Venugopal S, Hsiao C, Sonoda T, Weida-Pazos M, Chandler S: Homeostatic dysregulation in membrane properties of masticatory motoneurons compared to oculomotor neurons in a mouse model for Amyotrophic Lateral Sclerosis. Journal of Neuroscience. 2015, 35 (2): 707-720.
This study was supported by NIH grant NS071348 to S.H.C.
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Venugopal, S., Wiedau-Pazos, M. & Chandler, S.H. Early dysregulation of trigeminal motor pool excitability in a mouse model for neurodegenerative motoneuron disease. BMC Neurosci 16, P31 (2015). https://doi.org/10.1186/1471-2202-16-S1-P31
- Amyotrophic Lateral Sclerosis
- Motoneuron Disease
- Motor Pool
- Close Muscle
- Fast Fatigue