Cognitive deficits and negative symptoms associated with schizophrenia are poorly managed by current antipsychotics. In order to develop effective treatments, refining animal models of schizophrenia is essential. To address its multifactorial etiology, we developed a new 3-hit mouse model. This model was mostly concealing the glutamatergic deficit hypothesis of the pathology (underlying cognitive and negative deficits). Thus, a genetic susceptibility (serine racemase deletion) was associated to environmental stress (24h maternal separation at 9-day of age) and pharmacological treatment (phencyclidine 10 mg/kg/day, a glutamate receptor antagonist treatment from 8 to 10-week of age). The validity of this model was assessed in female mice by a behavioral experiment of positive-like, negative-like and cognitive deficits. Moreover, synaptic transmission and functional plasticity were also studied in CA1 hippocampal region of ex-vivo slices in a preliminary electrophysiological investigation.Our results showed that the 3-hit mice display positive-like symptoms (hyperlocomotion), spatial working memory deficits (reduced spontaneous alternation percentage in Y maze) and sociability deficits. Moreover, long-term potentiation (LTP) triggered by theta-burst (TBS), but not by high-frequency (HFS) stimulation, was impaired - suggesting a dysregulation of hippocampal GABAergic regulatory system.Our work confirms the usefulness of the 3-hit model to model cognitive deficits and negative-like symptoms. Such pattern of symptoms is observed in certain subtype of schizophrenia, accompanied by alteration in hippocampus functioning. The model therefore gathers powerful construct and face validities, which sustain an involvement of glutamate dysfunction in behavioral symptoms. The present data also highlight PCP-induced alterations in the hippocampus of glutamate- and GABA-mediated regulation.