Investigating the early changes in intrinsic properties and synaptic inputs in the vulnerable fast-type motoneurons of SOD1ᴳ⁹³ᴬ mouse model of Amyotrophic Lateral Sclerosis

  • Arauthy Gina Gnanasampanthan

Student thesis: Doctoral Thesis (PhD)


Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by the deterioration of upper and lower motoneurons (MNs), which leads to paralysis and death. Pathophysiological alterations in MN output have been shown at early postnatal stages in ALS model mice; however, it is unclear whether these changes are due to alterations in synaptic inputs or intrinsic MN properties. Here, we investigated the mechanisms contributing to altered MN output by using whole-cell patch clamp electrophysiology to study MN properties and synaptic inputs to MNs during the first two postnatal weeks in the SOD1ᴳ⁹³ᴬ mouse model of ALS. Our study targeted delayed firing, fast- type lumbar MNs that are vulnerable and degenerate in ALS. We observed increases in the frequency of mixed postsynaptic currents (PSCs) received by SOD1ᴳ⁹³ᴬ MNs and application of tetrodotoxin also showed increased frequency of action-potential independent miniature PSCs (mPSCs). When pharmacologically characterising the origin of mPSC, we observed a decrease in excitatory mPSC frequency and increases in both frequency and amplitude of inhibitory mPSC in fast-type SOD1ᴳ⁹³ᴬ MN.

Analysis of MN intrinsic properties, including capacitance, rheobase, persistent inward currents and post-discharge activity, revealed no significant changes in fast-type MNs of SOD1ᴳ⁹³ᴬ mice. However, a significant increase in the hyperpolarisation-activated inward current (Ih), an important factor driving recruitment and rebound depolarisation, was observed in two-week-old SOD1ᴳ⁹³ᴬ mice. Next, we investigated the distribution of excitatory and inhibitory post-synaptic density (PSDs) and their subsynaptic nanoclusters (NCs) in motoneuron rich area of lamina IX of SOD1ᴳ⁹³ᴬ mice. Super-resolution microscopy revealed decreases in both excitatory and inhibitory NCs size in SOD1ᴳ⁹³ᴬ. We found that although the density of inhibitory PSD is lower in the SOD1ᴳ⁹³ᴬ, there was no difference in the excitatory: inhibitory ratio (E:I) in the second postnatal week of SOD1ᴳ⁹³ᴬ mice.

Overall, early postnatal changes observed in synaptic inputs demonstrate an early role for synaptic dysfunction in SOD1 ALS. Changes in Ih and synaptic inputs may both contribute to improper MN output as the disease progresses. These early changes together could set up the neuronal network for failure which could lead to progressive degeneration of spinal MNs in SOD1ᴳ⁹³ᴬ ALS.
Date of Award29 Nov 2023
Original languageEnglish
Awarding Institution
  • University of St Andrews
SupervisorGareth Brian Miles (Supervisor)


  • Amyotrophic Lateral Sclerosis
  • Intrinsic properties
  • Motoneurons
  • Synaptic inputs
  • Whole-cell patch clamp

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