Epilepsy is a disease characterized by chronic seizures, but is associated with significant comorbidities between seizures including cognitive impairments, hyperactivity, and depression. To study this interictal state, we characterized the electrical, molecular, and behavior effects of chronic, neocortical interictal spiking in rats. A single injection of tetanus toxin into somatosensory cortex generated chronic interictal spiking measured by long-term video EEG monitoring and was correlated with motor activity. The cortical pattern of biomarker activation and the effects of blocking MAPK signaling on interictal spiking and behavior were determined. Interictal spiking in this model increases in frequency, size, and becomes repetitive over time, but is rarely associated with seizures. Interictal spiking was sufficient to produce the same molecular and cellular pattern of layer 2/3-specific CREB activation and plasticity gene induction as is seen in the human interictal state. Increasing spike frequency was associated with hyperactivity, demonstrated by increased ambulatory activity and preferential circling toward the spiking hemisphere. Loud noises induced epileptic discharges, identical to spontaneous discharges. Treatment with a selective MAPK inhibitor prevented layer 2/3 CREB activation, reduced the frequency of epileptic discharges, and normalized behavioral abnormalities, but had no effect on seizures induced by electrical kindling. These results provide insights into the development of interictal epileptic spiking, their relationship to behavior, and suggest that interictal and ictal activities utilize distinct molecular pathways. This model, that parallels recent observations in humans, will be useful to develop therapeutics against interictal spiking and its behavioral comorbidities.