Mice deficient for the peripheral myelin binding protein zero (P0-/-) show a progressive dysmyelinating neuropathy phenotypically resembling severe forms of Charcot-Marie-Tooth (CMT) disease. Traditionally, the progression of the disease was attributed to axonal loss, but the effect of chronic dysmyelination remains poorly understood. In this study, in vivo electrophysiological recordings were used to assess the function of both central and axonal components of spinal lumbar motoneurones in adult P0-/- mice.Three month old P0-/- mice (n=7) and wild type (WT) littermate controls (n=5) were anaesthetized with Hypnorm (0.315 mg/mL fentanyl-citrate + 10 mg/mL fluanisone), Midazolam (5 mg/mL), and sterile water, mixed in the ratio 1:1:2 (induction: 0.15mL/25g, maintenance: 0.05 mL/20 minutes, S.C.). Anaesthesia during surgery was assessed by the lack of reflexes to a short noxious pinch on the hind foot. Prior to recording, mice were ventilated before being paralysed with Pancuronium Bromide (0.01mg/h, I.P.). Anaesthesia after this was maintained using the same doses as previously necessary during the surgical procedures (ensuring a deep anesthesia) and its adequacy confirmed by the continuous monitoring of the heart rate. Intracellular recordings with sharp microelectrodes were made from identified spinal motoneurones (for detailed methods see Meehan et al. 2010). After end experiments, animals received an overdose of anesthesia and were perfused intracardially with 4% paraformaldehyde. Mean values are given with SD. Antidromic action potentials (APs) generated in the motor axons often failed to reach the soma in P0-/- (34/62 cells). Intracellular current injection into the soma of these cells, however, always resulted in somatic APs and repetitive firing was observed at high frequencies. Furthermore, rheobase, voltage threshold, input resistance, and AP amplitude and width were not significantly different (all P>0.05, Mann Whitney). Further investigation (including intra-axonal recordings) suggested that the axonal conduction failure could be aggravated by prolonged stimulation, consistent with axonal dysfunction rather than axonal loss. Recordings from motoneurone cell bodies of P0-/- mice did show some abnormalities: The amplitude of the post-spike after-hyperpolarization was increased (WT: 2.07±1.02mV (n=25), P0-/-: 2.50±0.65mV (n=22), Mann-Whitney: P=0.0311). There was also an earlier onset of the secondary range on I-f slopes (WT: 157±16Hz (n=11), P0-/-: 121±13Hz (n=18), Mann-Whitney: P<0.0001) and an increased ΔI (de-recruitment minus recruitment current) following triangular current injections (WT: -1.10±2.69nA (n=25), P0-/-: -0.19±2.44nA (n=35), Mann-Whitney: P= 0.0148), indicating increased activation of persistent inward currents. Our identification of a functional, thus potentially reversible, conduction failure in otherwise healthy motoneurones in P0-/- mice raises the hope that symptomatic treatments could be developed to improve motor function in CMT disease. Where applicable, experiments conform with Society ethical requirements