In this study, we test the hypothesis that monosynaptic connections between la afferents and spinal motoneurons are strengthened by chronic disuse. Impulse activity along the medial gastrocnemius (MG) nerve was blocked for 2 weeks using TTX delivered by an osmotic minipump to a Silastic cuff placed around the nerve. The duration and specificity of this block were confirmed by chronic EMG recordings from several triceps surae muscles. The effect of TTX-induced inactivity of presynaptic elements on EPSP amplitude was distinguished from the effect of treating the postsynaptic target by comparing the results from heteronymous synaptic connections, where only one or the other element was treated. After 2 weeks of synaptic inactivity, the heteronymous EPSPs generated by MG la afferents in lateral gastrocnemius/soleus (LG-Sol) motoneurons were significantly (p less than 0.005) larger than control values (48%). Sample differences in rheobase current and half-afterhyperpolarization, both of which may covary with EPSP amplitude, did not account for the differences between groups. Segregation of the two samples of motoneurons by rheobase current identified the increase as being confined to those LG-Sol cells whose rheobase fell below 10 nA. In addition, EPSPs generated by untreated LG-Sol la afferents in treated MG motoneurons were significantly enhanced (39%, p less than 0.05). Thus, TTX treatment of either presynaptic or postsynaptic elements increases synaptic strength. This increase in monosynaptic EPSP amplitude following TTX- induced inactivity may reflect an alteration intrinsic to the la afferent to motoneuron synapse, but influences from extrinsic sources cannot be discounted.