AKT-2 Heterozygous Mice Exhibit a Unique Behavioral Phenotype Relevant to Schizophrenia

Background: The AKT family consists of three highly homologous kinases, AKT-1, AKT-2 and AKT-3, encoded by different genes. Polymorphic variation in AKT-1 has been associated with reduced AKT expression in schizophrenia and inefficient prefrontal cortical (PFC) function in healthy individuals. Studies using AKT-1 knockout mice, suggest a critical role for AKT-1 in synaptic development and PFC and hippocampal function. Data is absent on the neurological role of AKT-2 and -3 and expression in schizophrenia, but it’s reported that all AKT isoforms are highly expressed in brain and that AKT-3 deletion impacts cortical development. Our project aims to examine the consequences of AKT-2 genetic deletion on neurodevelopment and adult brain function using murine behavior profiles related to schizophrenia, including learning, memory and cognition. Methods: AKT-2 heterozygous (floxed-POU34 germline HETS-B6.CgAKT2tm1.1Mbb/J) male mice (N=10-12) were tested for general health, locomotor activity, temporal order object recognition and prepulse inhibition (PPI) of startle. PPI provides an operational measure of sensorimotor gating; it’s disrupted in schizophrenia patients and their unaffected relatives. Also cognitive impairment is one of the core features of the disorder. Results: AKT-2 heterozygous mice display disrupted PPI (F1,109=28.21,p<0.0001) and impaired memory (p<0.0001). Moreover, they exhibit normal baseline locomotor activity, but demonstrate an anxiety profile, which includes inhibited forepaw reaching and increased positional passivity and rearing events (p=0.001). Conclusions: Our data indicate that AKT-2 plays a role in brain development and function, its deletion impacts behavioral profiles affected in schizophrenia. Further investigations in schizophrenia are warranted.