Phosphatidylinositide Dependent Kinase Deficiency Increases Anxiety and Decreases GABA and Serotonin Abundance in the Amygdala

Abstract

Pathological anxiety is paralleled by deficits in serotonergic and GABAergic neurotransmission in the amygdala. Conversely, anxiety disorders and depression may be reversed by brain-derived neurotrophic factor (BDNF). BDNF signaling involves Phosphatidylinositol 3-Kinase / 3-phosphoinositide-dependent protein kinase 1 (PI3K/PDK1). We thus hypothesized that impaired function of PDK1 might be associated with increased anxiety and concomitant neurotransmitter changes. Here we used the hypomorphic PDK1^hm mouse to investigate anxiety behavior in different settings: PDK1^hm mice differed from Wt littermates PDK1^WT in several behavioral measures related to anxiety and exploration, namely in the open field, dark-light box, O-maze and startle response. Further we analyzed the brain substrate underlying this phenotype and found significantly decreased GABA, taurine and serotonin concentrations in the amygdala and olfactory bulb of PDK1^hm mice, while BDNF and nerve growth factor (NGF) concentrations were not significantly different between PDK1^hm and PDK1^WT mice. These results suggest that impaired PI3K signaling in the PDK1^hm mouse reduces concentrations of GABA and serotonin in anxiety related brain regions and can serve as a molecular substrate for behavior indicative for anxious and depressive-like mood states.

Molecular Mechanisms of Depression: Perspectives on New Treatment Strategies

“…At least FGF-2 can be upregulated by antidepressant treatment [157]. It has been discussed recently, that BDNF might well signal through phosphoinositol dependent kinase 3, Akt and glycogen synthase kinase (GSK3) pathways [158], which has been supported also by our own data [159,160,161]. …”

Phase Ib Study of Buparlisib plus Trastuzumab in Patients with HER2-Positive Advanced or Metastatic Breast Cancer That Has Progressed on Trastuzumab-Based Therapy

“…A recurrent side effect associated with buparlisib treatment was the occurrence of psychiatric adverse events, and this observation is likely associated with penetration of buparlisib across the blood-brain barrier and inhibition of PI3K/AKT/mTOR signaling in the CNS (40,41). In separate studies, dysregulation of the PI3K pathway has been associated with changes in serotonin levels and in psychiatric disturbances, such as anxiety and depression (42)(43)(44). In the current study, the median time-to-first occurrence of psychiatric adverse events (regardless of study drug relationship) was 7.1 weeks (7.1 weeks in the 50-mg/day cohort and 6.1 weeks in the 100-mg/day cohort).…”

Targeting the PI3K/Akt/mTOR pathway in castration-resistant prostate cancer

“…Neuropsychiatric adverse events, including reversible and generally mild-to-moderate mood alterations and depression were seen with BKM120 treatment and are thought to reflect the ability of BKM120 to cross the blood-brain barrier and inhibit the PI3K/Akt/mTOR pathway in the brain (Maira et al 2012a, Nanni et al 2012. In support of this, low/dysfunctional PI3K/Akt/mTOR signaling has been shown to reduce the concentration of the neurotransmitters GABA and serotonin in anxiety-related brain regions such as the amygdala and has been linked to anxiety and depression (Ackermann et al 2008). Mood alterations observed in this phase I study of BKM120, therefore, highlight the need for close monitoring for psychiatric symptoms in patients treated with PI3K/Akt/mTOR inhibitors.…”