Abstract A lesion of the entorhinal cortex produces a loss of more than 80% of the synapses in the outer molecular layer of the hippocampus in the rat. However, this synaptic loss is transient. Beginning a few days after denervation, new synapses are formed, virtually replacing the lost inputs within two months. Synaptic remodelling induced by entorhinal cortex lesion is associated with specific modifications of various neurotransmitters, hormones and growth factors. Many of these substances act at membrane bound-receptors to induce the hydrolysis of phosphatidylinositols generating various inositol phosphates. Some of the key members of this family include inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakispho-sphate and inositol hexakisphosphate which are all associated with the maintenance Ca 2+ homeostasis. To investigate the potential roles and/or alterations of inositol phosphates in entorhinal cortex lesions-induced neuronal plasticity, we quantified specific receptor sites for inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate and inositol hexakisphosphate using their respective tritiated ligands, at different periods post-lesion corresponding to the degenerative and subsequent reinnervation phases. [ 3H]inositol 1,4,5-trisphosphate binding sites are maximally increased (30%) between two and eight days post-lesion in the hippocampal formation on both sides of the lesion. In the cortex, [ 3H]inositol 1,4,5-trisphosphate binding increased also bilaterally following the lesion. Changes in [ 3H]inositol 1,3,4,5-tetrakisphosphate binding are delayed and reduced (20% increase) in magnitude compared to these seen for [ 3H]inositol 1,4,5-trisphosphate binding. The maximal peak in [ 3H]inositol 1,3,4,5-tetrakisphosphate binding is observed between eight and 14 days after the lesion in the hippocampal formation and the cortex. On the other hand, decreases in [ 3H]inositol hexakisphosphate binding (up to 30%) in the parietal cortex and the pyramidal cell layer of the hippocampal formation were observed between 14 and 30 days post-lesion. Taken together, these results suggest that inositol 1,4,5-trisphosphate, inositol 1,3,4,5-tetrakisphosphate and inositol hexakisphosphate receptors can be regulated in vivo following entorhinal cortex lesions. A unique time course is observed for each inositol phosphate receptor site studied. This finding supports the hypothesis suggesting that each inositide is differentially involved in the process of neuronal plasticity observed following deafferentation in the entorhinal cortex of rats. The bilateral changes in unilaterally lesioned animals is consistent with secondary synapse turnover associated with deafferentation.