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In the present study, we evaluated a multiple-hit animal model of schizophrenia in an attempt to capture the complex interactions among various adverse developmental factors in schizophrenia. Sprague–Dawley rats were assigned to receive either repeated daily 3-h maternal separation for eight days (first “hit”) on postnatal days (PND) 3 to 10, and/or avoidance conditioning for six days (second “hit”) on PND 49–56, and/or repeated phencyclidine treatment (third “hit”, 3.0 mg/kg, sc) immediately after each daily avoidance conditioning. Prepulse inhibition (PPI) of acoustic startle reflex was assessed at late adolescence (PND 41–43) and early adulthood (PND 62–63). The change in %PPI from the adolescence phase to adulthood phase was used to index the maturation-related improvement of sensorimotor gating ability. Maternal separation, avoidance conditioning, and PCP treatment had a complex three-way interaction on the functional improvement of sensorimotor gating. Maternal separation impaired PPI improvement preferentially in the saline rats that were not subjected to avoidance conditioning. Avoidance conditioning had no effect on PPI improvement in the non-maternally separated rats, but restored the maternal separation-induced disruption. However, this restoration effect was abolished by PCP treatment. The present study also identified a number of behavioral, emotional and learning abnormalities caused by these three developmental insults which may precede their interactive disruption of normal development of sensorimotor gating ability.