The Intrinsic Hyperexcitability of SMA Motor Neurons is a Result of Dysfunctional Spinal Circuitry

Abstract

Spinal muscular atrophy (SMA) - the most common genetic cause of death in infancy - is a motor neuron disease caused by reduced expression of the survival motor neuron (SMN) protein. It is currently unknown why reduction in SMN, leads to selective motor deficits and muscle weakness. Using the SMA-Δ7 mouse model, we have previously reported that the sensory-motor circuit is dysfunctional early in the disease and precedes any motor neuron loss. Motor neurons in the L1 segment, innervating proximal muscles, are abnormally hyperexcitable and more affected than L5 motor neurons, innervating distal hindlimbs early after birth. To test whether this hyperexcitability is either due to synaptic dysfunction or SMN deficiency per se in motor neurons, we recorded intracellularly from L5 motor neurons at a time (P4) when there was no significant functional synaptic impairment.We employed the in vitro intact spinal cord preparation. Whole-cell patch clamp recordings revealed that the intrinsic properties of SMA L5 motor neurons were not significantly different than wild type (WT) age-matched counterparts. The passive membrane property of input resistance was on average 72.7±18.1 MΩ in WT (n=10) and 53.9±21.7 MΩ in SMA (n=5) motor neurons. Similarly, the time constant was 1.9±0.5 ms in WT and 2.0 ± 0.7 ms in SMA. Furthermore, the active membrane properties of: Rheobase (WT: 0.7±0.2 nA; SMA:0.8±0.2 nA), Vthreshold (WT: −31.6±3.7 mV; SMA: −33.6±2.6 mV), action potential amplitude (WT: 72.8±5.2 mV; SMA: 73.2±3.6 mV) and rate of rise (WT: 48.8±6.2 mV/ms; SMA: 40.2±10.0 mV/ms) were not significantly different (t-test).These results indicate that the intrinsic hyperexcitability of SMA motor neurons stems from dysfunctional spinal circuits and raise the possibility that SMA may be a disease of motor circuits acting via non-cell autonomous mechanisms.