The RISE model is an effective system to study the underlying molecular and cellular mechanisms involved in the initiation and maintenance of epilepsy in vivo. Here we profiled the expression of excitatory and inhibitory neurotransmitter receptor subunits and synaptic scaffolding proteins in the hippocampus and temporal lobe and compared these changes with alterations in network activity at specific timepoints during epileptogenesis. Significant changes occurred in all of the ionotropic glutamate receptor subunits tested during epilepsy induction and progression and the profile of these changes differed between the hippocampus and temporal lobe. Notably, AMPAR subunits were dramatically decreased during the latent phase of epilepsy induction, matched by a profound decrease in the network response to kainate application in the hippocampus. Moreover, decreases in the GABAAβ3 subunit are consistent with a loss of inhibitory input contributing to the perturbation of excitatory/inhibitory balance and seizure generation. These data highlight the synaptic reorganisation that mediates the relative hypoexcitability prior to the manifestation of seizures and subsequent hyperexcitability when spontaneous seizures develop. These patterns of changes give new insight into the mechanisms underpinning epilepsy and provide a platform for future investigations targeting particular receptor subunits to reduce or prevent seizures.