Schizophrenia (SZ) is a complex genetic, neurodevelopmental disorder characterized by cognitive dysfunction. The etiological basis of cognitive deficits is unclear, but evidence details abnormalities in genes that converge on AKT signaling and the regulation of neuronal/synaptic homeostasis, highlighting a target pathway for advanced psychiatric drug development. Genetic studies in humans and mice demonstrate that AKT1 is associated with risk for SZ, abnormal prefrontal cortical (PFC) and hippocampal function and deficits in learning, memory and attention. Furthermore, recent genome-wide association data in SZ highlight a significant role for genetic variation in the AKT3 gene in risk. The neurobiological mechanisms remain unknown. The biology of AKT signaling is complex, involving three homologous members (AKT1, AKT2, and AKT3), encoded by independent genes, each playing distinct and functionally interrelated roles in cell growth, metabolism and survival. Despite the knowledge that all AKT isoforms are highly expressed in brain, AKT3 mutations are linked to abnormal brain development, and AKT signaling is deficient in SZ, the mechanistic role of the individual AKTs and the pathway as a whole in physiological processes relevant to neuronal development and function, cognition and psychiatric illness, is poorly understood. Moreover, dopamine D2 receptor antagonists, the main clinically effective antipsychotic drugs, enhance AKT activity in vivo, suggesting a molecular mechanism relevant to therapeutic action. However, it is unclear which isotypes are targeted and why current neuroleptics fail to treat cognitive dysfunction in the disorder. Relevantly, our recent work has identified that enhancement of the AKT pathway via selective pharmacological modulation of the PI3Kinase, p110?(with IC87114), has antipsychotic properties in rodent models of SZ. Significantly, our preliminary data extend this to show that the drug has cognitive enhancing benefits. These data suggest that direct, pharmacological enhancement of AKT signaling may represent a refined therapeutic approach to treating cognitive dysfunction in SZ. In this proposal we will use mice with single genetic deletions of Akt1, Akt2 and Akt3 to determine the mechanistic role of AKT isotypes in cortical circuit development, using whole-cell in-vitro slice electrophysiology and proteomic approaches. We will also define the contribution of each AKT isoform to cognitive and behavioral development as it relates to SZ using a murine preclinical neurocognitive test battery. Finally, we will examine whether p110?nhibition (utilizing IC87114) is an effective mechanism to improve PFC-dependent cognitive deficits associated with Akt1, Akt2 or Akt3 deficiency and determine how positive outcomes are mechanistically related to isoform-specific AKT signaling. Overall these studies will provide important insight into the neurobiological roles of individual Akt isotypes and directly impact the potential use of PI3K/AKT-based therapeutic regimens for treating cognitive deficits in SZ, providing an important translational framework for understanding SZ pathophysiology and its treatment.
Understanding how genes affect brain development and behavior is necessary to determine origins of disease and for the development of new treatments for psychiatric and cognitive disorders such as schizophrenia. The present proposal will investigate the neurobiological role of a critical gene pathway in the brain (AKT), in order t better understand the role of the genes in brain development, behavior and response to novel treatment therapies. Advances in the identification and understanding of novel drug targets may affect the lives of a large number of people suffering from these devastating disorders.
| Paterson, Clare; Law, Amanda J (2018) Toward Better Strategies for Understanding Disrupted Cortical Excitatory/Inhibitory Balance in Schizophrenia. Biol Psychiatry 83:632-634 |
| Howell, Kristy R; Floyd, Kirsten; Law, Amanda J (2017) PKB?/AKT3 loss-of-function causes learning and memory deficits and deregulation of AKT/mTORC2 signaling: Relevance for schizophrenia. PLoS One 12:e0175993 |
| Papaleo, Francesco; Yang, Feng; Paterson, Clare et al. (2016) Behavioral, Neurophysiological, and Synaptic Impairment in a Transgenic Neuregulin1 (NRG1-IV) Murine Schizophrenia Model. J Neurosci 36:4859-75 |
| Jenkins, A K; Paterson, C; Wang, Y et al. (2016) Neurexin 1 (NRXN1) splice isoform expression during human neocortical development and aging. Mol Psychiatry 21:701-6 |
