Ia glutamatergic synapses on spinal motoneurons (MNs) are functionally and structurally impaired in the SOD1 mouse model of ALS at a presymptomatic stage. However, we do not know the consequence of such a synaptic impairment on intracellular activity-dependent signaling. To investigate this issue we focused on activity-dependent signaling pathways: CaMKIV/CREB and ERK/S6. Unilateral small vibrations at high frequencies were applied to the Achilles tendon in order to activate the spindle primary endings in triceps surae (TS), eliciting Ia inputs to homonymous motoneurons. In vivo intracellular recordings of TS MNs showed that the vibration-induced EPSPs mostly remained below the threshold for spiking. We injected CTb bilaterally in TS muscles and compared CTb+ TS MNs from vibrated vs. non-vibrated side. The vibration-induced Ia EPSPs induced a phosphorylation of CREB, S6 and CaMKIV in MNs from WT mice but not in the SOD1 mice, indicating that in the latter, Ia inputs are uncoupled from activity-dependent signaling pathways. This impairment does not seem to be caused by the reduced EPSPs size in SOD1 mice since treatment with Ampakine, known to prolong the opening of AMPA receptors, increased the EPSP size but does not restore phosphorylation of CREB, S6 and CaMKIV after vibrations. However, treatment with selective phosphodiesterase-4 inhibitor (Rolipram) restores CREB and S6 phosphorylation in response to the Ia vibration-induced inputs. This occurs despite Rolipram does not increase the size of Ia EPSPs. We are further investigating the mechanisms of the uncoupling between synaptic activity and activity-dependent pathways in SOD1 animals. Funding: NCN 2019/35/B/NZ4/02058