Akt-mTOR hypoactivity in bipolar disorder gives rise to cognitive impairments associated with altered neuronal structure and function

• Published in: Neuron (Cambridge, Mass.) Mass.), 2021-05, Vol.109 (9), p.1479-1496.e6
• Main Authors: Vanderplow, Amanda M., Eagle, Andrew L., Kermath, Bailey A., Bjornson, Kathryn J., Robison, Alfred J., Cahill, Michael E.
• Format: Article
• Language: English
• Subjects: akt; AKT protein; autophagy; Bipolar disorder; Bipolar Disorder - metabolism; Bipolar Disorder - pathology; Bipolar Disorder - physiopathology; cognition; Cognitive ability; Cognitive Dysfunction - metabolism; Cognitive Dysfunction - pathology; Cognitive Dysfunction - physiopathology; Consortia; dendritic spine; Female; Genes; Genomics; Humans; Kinases; Male; memory; Mental disorders; mTOR; Neural networks; Neurons - pathology; Phenotypes; Phosphorylation; Prefrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - pathology; Prefrontal Cortex - physiopathology; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Psychosis; Rapamycin; Schizophrenia; Structure-function relationships; synapse; TOR protein; TOR Serine-Threonine Kinases - metabolism; ulk1
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.03.008

The Akt family of kinases exerts many of its cellular effects via the activation of the mammalian target of rapamycin (mTOR) kinase through a series of intermediary proteins. Multiple lines of evidence have identified Akt-family kinases as candidate schizophrenia and bipolar disorder genes. Although dysfunction of the prefrontal cortex (PFC) is a key feature of both schizophrenia and bipolar disorder, no studies have comprehensively assessed potential alterations in Akt-mTOR pathway activity in the PFC of either disorder. Here, we examined the activity and expression profile of key proteins in the Akt-mTOR pathway in bipolar disorder and schizophrenia homogenates from two different PFC subregions. Our findings identify reduced Akt-mTOR PFC signaling in a subset of bipolar disorder subjects. Using a reverse-translational approach, we demonstrated that Akt hypofunction in the PFC is sufficient to give rise to key cognitive phenotypes that are paralleled by alterations in synaptic connectivity and function. •A reduction in Akt-mTOR signaling occurs in the PFC of male bipolar disorder subjects•Akt hypofunction reduces synaptic structural and functional plasticity in the PFC•Akt hypofunction is sufficient to impair PFC-mediated cognition The biochemical changes that contribute to bipolar disorder pathophysiology remain largely unknown. Cahill et al. reveal a reduction in the activation of the Akt-mTOR pathway in the prefrontal cortex of bipolar disorder subjects. Cahill et al. demonstrate that reduced activity of this pathway causes cognitive and synaptic phenotypes.