Summary: Disruptions in the Akt protein can produce brain changes that match those seen in bipolar disorder.
Source: University of Wisconsin–Madison
Bipolar disorder affects millions of people, causing dramatic mood swings and, in many cases, cognitive issues such as memory problems.
While many genes contribute small effects to bipolar disorder, how those genetic differences translate into the disorder’s symptoms has been unclear. New research from the University of Wisconsin–Madison identifies a clear biological mechanism: reduced activity of the Akt signaling pathway in the prefrontal cortex, a change that can produce the cognitive and structural brain alterations linked to bipolar disorder.
Akt is a kinase, a protein that attaches phosphate groups to other proteins. These phosphate tags act as molecular switches, turning other proteins on or off and thereby shaping essential cellular functions. In neurons, Akt activity affects how cells communicate — processes that influence memory, attention and mood. When Akt-mTOR signaling is active, many target proteins carry phosphate tags; when the pathway is less active, those modifications are absent.
Researchers led by Michael Cahill at UW–Madison examined postmortem prefrontal cortex tissue from donors with schizophrenia, bipolar disorder with psychosis, bipolar disorder without psychosis, and from healthy donors. By measuring phosphorylation patterns on proteins regulated by Akt, the team assessed overall Akt-mTOR pathway activity in this brain region that is crucial for high-level cognition and is affected in both bipolar disorder and schizophrenia.
Contrary to expectations — since genetic links between Akt and schizophrenia are strong — the researchers found a specific decrease in Akt-mTOR activity only in the prefrontal cortex of men with bipolar disorder without psychosis. This sex- and subgroup-specific finding highlights the biological diversity of psychiatric conditions and underscores the need to study groups separately rather than assuming a single common mechanism across diagnoses.
To test whether reducing Akt activity could cause functional changes similar to those seen in patients, the team used viral vectors in mice to deliver defective Akt proteins into the prefrontal cortex. These defective proteins acted as dominant negatives, interfering with normal Akt signaling. Mice with suppressed Akt function showed clear impairments in memory-related tasks: they no longer preferentially investigated objects or environments that had been changed — a sign that recognition and novelty detection were impaired.
Importantly, the mice did not display abnormal social behavior, indicating that Akt hypofunction specifically affected certain cognitive processes rather than all high-level behaviors. Anatomical examination revealed that dendritic spines — the small protrusions on neurons where most excitatory synapses form — were reduced in number. Fewer dendritic spines mean fewer points of contact between neurons, which can impede information flow through neural circuits and help explain memory deficits.
These findings create a direct link from altered Akt signaling to two features commonly observed in people with bipolar disorder: cognitive impairment and weakened neuronal connectivity. The work suggests that targeting Akt-mTOR signaling pharmacologically could be a promising avenue to treat the cognitive symptoms of bipolar disorder, which are often under-recognized and undertreated.
However, the study also raises important unanswered questions. The reduced Akt-mTOR activity was observed in men with bipolar disorder without psychosis but not in women with bipolar disorder, nor in people with bipolar disorder with psychosis or in those with schizophrenia. These differences indicate that other genes and pathways likely play larger roles in those groups and that sex-specific mechanisms may be important.
Future work from Cahill’s lab will trace specific neural circuits to determine how Akt signaling controls synaptic structure and memory. Understanding how subtle genetic variations cause major differences in cognition and behavior will be essential to develop targeted treatments that address the core cognitive disabilities associated with bipolar disorder.
Funding: This research was supported in part by the National Institutes of Health (grants R21MH125227 and R01MH111604).
About this bipolar disorder research news
Source: University of Wisconsin–Madison
Contact: Eric Hamilton – University of Wisconsin–Madison
Image: The image is in the public domain
Original Research: Closed access. “Akt-mTOR hypoactivity in bipolar disorder gives rise to cognitive impairments associated with altered neuronal structure and function” by Michael E. Cahill et al., Neuron.
Abstract
Akt-mTOR hypoactivity in bipolar disorder gives rise to cognitive impairments associated with altered neuronal structure and function
Highlights
- • Reduced Akt-mTOR signaling occurs in the prefrontal cortex (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
Summary
The Akt family of kinases exerts many effects through activation of the mammalian target of rapamycin (mTOR) via intermediary proteins. Genetic and functional evidence has implicated Akt-family kinases in risk for schizophrenia and bipolar disorder. Dysfunction of the prefrontal cortex is a hallmark of both conditions, but prior studies had not comprehensively assessed Akt-mTOR pathway activity in the human PFC across these disorders.
This study measured activity and expression of key Akt-mTOR proteins in PFC samples from individuals with bipolar disorder and schizophrenia, across two PFC subregions. Results reveal reduced Akt-mTOR PFC signaling in a subset of bipolar disorder subjects. Using reverse-translational mouse models, the researchers demonstrated that Akt hypofunction in the PFC is sufficient to cause cognitive deficits that coincide with disruptions in synaptic connectivity and function, linking gene-level variation to clinically relevant brain changes.