BLOCKING OF NMDA RECEPTORS DURING A CRITICAL STAGE OF DEVELOPMENT REDUCES THE EFFECTS OF NERVE INJURY AT BIRTH ON MUSCLES AND MOTONEURONS

Blocking of NMDA receptors during a critical stage of development redu ces the effects of nerve injury at birth on muscles and motoneurones. Injury to the sciatic nerve at birth causes many motoneurones to soleu s and extensor digitorum longus (EDL) muscles of rats to die. This is reflected in a reduction of motor units in these muscles. In the soleu s only 4 (12.3%) motor units remain while 10 (24.3%) remain in the EDL , showing that soleus alpha motoneurones are more sensitive to nerve i njury at birth. Treatment with MK-801, an NMDA receptor blocker, rescu es a proportion of motor units in both muscles, so that in the soleus 11 (36%) and in the EDL 17 (42%) of motor units survive. This loss of motor units results in muscle weakness and a reduction in force of bot h muscles. Treatment with MK-801 reduces the effect of nerve injury, s o that muscles of treated animals are stronger and weigh more. Cross-s ectional area and muscle fibre number in EDL muscles were assessed and found to be dramatically reduced after nerve injury at birth, so that the area was 20% of control, with only 13% of fibres remaining. Moreo ver the majority of the remaining EDL muscle fibres which are normally fast are converted into slow type I fibres, with 68% of fibres expres sing slow myosin compared with 3% in control EDL muscles. In animals t reated with MK-801 only 47% of muscle fibres are lost after nerve inju ry at birth, hence the area of the muscle is greater (51% of control). The change of muscle phenotype induced by nerve injury is prevented a nd the muscle fibre composition resembles that of normal EDL muscles i n that 4% of muscle fibres express slow myosin compared with 3.5% in c ontrol EDL muscles. Thus, blocking NMDA receptors with MK-801 shortly after nerve injury at birth reduces the loss of motor units and this i s directly reflected in an improved performance of the affected muscle s.