Effective connectivity of akt1-mediated dopaminergic working memory networks and its relationship to the pharmacogenetics of cognition in schizophrenia

Abstract

Background: Working memory (WM) integrates and manipulates information across time, engaging a network of prefrontal, parietal and sub-cortical brain regions. While cortical dopamine (DA) enhances signal-to-noise tuning at the neuronal level, less is known about the genetic control of DA-associated signaling mechanisms and their impact in distributed brain networks during WM. Here, we examined functional genetic variants in COMT, DRD2 and AKT1 impacting brain DA bioavailability, D2 receptor function and its downstream signal transduction, and studied their influence across prefrontal-subcortical-parietal networks during segregated WM maintenance and manipulation events. Methods: We first examined 46 healthy subjects as they engaged an event-related numerical WM task in a GE 3T MRI scanner. The maintenance task events involved arrays of 2 or 4 numbers, while the manipulation events involved performing arithmetic operations on 1 or 2 of the maintained array of numbers. Subjects were genotyped for putatively functional polymorphisms in AKT1 rs1130233 (Tan et al 2008), DRD2 rs1076560 (Bertolino et al 2009) and COMT Val158Met (Egan et al 2001). Dynamic causal models (DCM; Friston et al 2003) of effective connectivity in prefrontal-parietal-striatal regions of interest in these task phases were examined. In translating these D2- AKT1 effects to cognition in schizophrenia, we tested for DRD2 and AKT1 pharmacogenetic effects on antipsychotic dose in a sample of schizophrenia patients (n=111). Results: Using dynamic causal modeling (DCM) of effective connectivity in fMRI (n=46 healthy controls), we found that COMT-Met individuals with putatively greater cortical DA bioavailability showed relatively stronger prefrontal-to-parietal and prefrontal-to-striatal connectivity during respective WM maintenance and manipulation processes (p<0.05). On the other hand, functional polymorphisms in DRD2 and AKT1 selectively impacted prefrontal-to-striatal connectivity (minor allele-carriers with relatively reduced effective connectivity, p<0.05) during WM manipulation events. Regional prefrontal activation also showed interactions between COMT and AKT1 (p<0.005 uncorrected), and between DRD2 and AKT1 (p<0.001 uncorrected) functional variants, consistent with the role DRD2-AKT1 coupling may play in the prefrontal-subcortical control of information gating and updating during WM manipulation. To the extent that DRD2- AKT1 might impact cognition in schizophrenia and is a target for antipsychotic drug action, we also found that the same DRD2 and AKT1 variation predicted dose-response relationships between antipsychotic drug treatment and illness-related IQ change (n=111 patients, p<0.05). Discussion: We suggest that genetic differences in dopaminergic neural signaling impact communication and information processing in prefrontal brain systems that may be relevant to individual variation in schizophrenia treatment and cognitive outcome.