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 reduces the effects of nerve injury at birth on muscles and motoneurones. Injury to the sciatic nerve at birth causes many motoneurones to soleus and extensor digitorum longus (EDL) muscles of rats to die. This is reflected in a reduction of motor units in these muscles. In the soleus 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 injury at birth. Treatment with MK-801, an NMDA receptor blocker, rescues 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 both muscles. Treatment with MK-801 reduces the effect of nerve injury, so that muscles of treated animals are stronger and weigh more. Cross-sectional 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. Moreover the majority of the remaining EDL muscle fibres which are normally fast are converted into slow type I fibres, with 68% of fibres expressing slow myosin compared with 3% in control EDL muscles. In animals treated with MK-801 only 47% of muscle fibres are lost after nerve injury at birth, hence the area of the muscle is greater (51% of control). The change of muscle phenotype induced by nerve injury is prevented and the muscle fibre composition resembles that of normal EDL muscles in that 4% of muscle fibres express slow myosin compared with 3.5% in control EDL muscles. Thus, blocking NMDA receptors with MK-801 shortly after nerve injury at birth reduces the loss of motor units and this is directly reflected in an improved performance of the affected muscles.