The “DA hypothesis” for schizophrenia has enjoyed a resurgence of interest, and increasing evidence links Akt to DA related behaviors, yet key molecular mechanisms linking Akt to DA homeostasis have been elusive. Given evidence for a role of Akt in the regulation of NET expression and function in cortex and evidence that NET transports DA in this brain area, it has been our priority to develop a compelling experimental model to uncover a molecular link between Akt and cortical DA homeostasis. Here, we conducted the first studies, to our knowledge, in an animal model where a genetic deletion that disrupts Akt phosphorylation enhances expression of NET and leads to a cortical hypodopaminergic phenotype with schizophrenia-linked behavioral consequences.
Our data are consistent with pathophysiological models of schizophrenia that emphasize “hypofrontality” of DA systems. Given the role of NET in DA clearance in prefrontal synapses 
, Akt-linked changes in NET expression may thereby translate to cognitive deficits and negative symptoms 
. These data, as well as our proof-of-principle results in mice, lead to the compelling hypothesis that NET inhibition would have therapeutic potential to selectively enhance DA tone in the prefrontal cortex and perhaps alleviate negative symptoms. Consistent with this reasoning, several clinical trials are currently investigating NET blockers for cognitive deficits in patients with schizophrenia.
Our data demonstrate that neuronal mTORC2 dysfunction is sufficient to generate cortical hypodopaminergia and schizophrenia-linked behaviors. In particular, we show that genetic mTORC2 disruption impairs PPI, a schizophrenia-linked phenotype, which has been validated in genetic mouse models of the disorder 
. An emerging body of evidence associates Akt phosphorylation deficits with mental illness in humans, giving our findings of impaired Akt phosphorylation in mice more translational viability 
. For example, studies show diminished Akt1 protein content in lymphocytes of patients with schizophrenia 
. In concert with our findings, candidate gene approaches aimed at identifying genetic variation in proteins associated with mTORC2/Akt signaling pathways, including rictor and other mTORC2 subunit proteins like mSin1 
, may yield new insights into the genetic basis of mental illness.
While DA is classically implicated in the pathogenesis of schizophrenia, concepts of neurotransmitter dysfunction in this disease process are constantly evolving. This is reflected by popular glutamatergic and recently proposed revisions to dopaminergic hypotheses of schizophrenia 
. However, the role of elevated cortical NE, while not typically emphasized, should not be overlooked. Indeed, findings of elevated NE in CSF of patients with schizophrenia, which led to noradrenergic hypotheses of schizophrenia in the early 1980s 
, support our model by which increased cortical NET expression leads to increased NE content but decreased DA content. While the sensitivity of these measurements to acute stressors made the reproducibility and reliability of these methods in the aforementioned studies questionable, a role for elevated NE in the development of schizophrenia-like phenotypes in humans cannot be completely ruled out. Indeed, our current findings, as well as others, intimately and mechanistically link DA alterations together with NE changes 
. As a recent revision to the DA hypothesis of schizophrenia suggests, schizophrenia could be conceptualized as a disease where DA dysfunction is a “final common pathway” that can be elicited by a number of more proximal causes, including both genetic and epigenetic factors and disruption in other neurotransmitter systems 
, and including, as we propose here, increased NET function.
Schizophrenia is thought to arise from rather complex gene-environment interactions, and therefore, acquired (rather than monogenetic) dysfunction in mTORC2/Akt signaling is a particularly intriguing mechanism. For example, acquired Akt defects are associated with impaired regulation of blood glucose and diabetes, which is overrepresented in first episode, medication-naive patients with schizophrenia 
. mTORC2/Akt signaling also provides a promising portal into “multiple hit” models of schizophrenia, as Akt is positioned to interact with other candidate genes such as neuregulin-1 and COMT 
as well as environmental risk factors for schizophrenia including obstetric complications and early life stressors 
. The effects of neuronal mTORC2 dysfunction on NET expression observed in our study ultimately illustrates a potential molecular mechanism to link disparate genetic and environmental factors (i.e. obesity/diabetes/insulin resistance) to dysfunction in a putative “final common pathway” of schizophrenia, namely alterations in DA signaling 
. Indeed, while more remains to be learned about mTORC2, deficiencies in Akt signaling even in “healthy” individuals are associated with impaired prefrontal cortex activation on working memory tasks 
and proneness to psychosis, suggesting a subtle influence on brain function and behavior that may require other genetic and environmental hits to result in clinical disease. Thus, our data provide one molecular mechanism, NET regulation, towards a framework linking environmental stressors and/or lifestyle factors to mTORC2/Akt signaling and ultimately to DA-dependent behaviors. Our studies provide a potential molecular mechanism linking Akt dysfunction to a schizophrenia-like phenotype and suggest the viability of targeting both Akt phosphorylation and NET as pharmacotherapies for schizophrenia.