A role for Akt and glycogen synthase kinase-3 as integrators of dopamine and serotonin neurotransmission in mental health

Abstract

Mental illnesses, such as bipolar disorder, attention-deficit/hyperactivity disorder, depression and schizophrenia are a major public health concern worldwide. Several pharmacologic agents acting on monoamine neurotransmission are used for the management of these disorders. However, there is still little understanding of the ultimate molecular mechanisms responsible for the therapeutic effects of these drugs or their relations with disease etiology. Here I provide an overview of recent advances on the involvement of the signalling molecules Akt and glycogen synthase kinase-3 (GSK3) in the regulation of behaviour by the monoamine neurotransmitters dopamine (DA) and serotonin (5-HT). I examine the possible participation of these signalling molecules to the effects of antidepressants, lithium and antipsychotics, as well as their possible contribution to mental disorders. Regulation of Akt and GSK3 may constitute an important signalling hub in the subcellular integration of 5-HT and DA neurotransmission. It may also provide a link between the action of these neurotransmitters and gene products, like disrupted in schizophrenia 1 (DISC1) and neuregulin (NRG), that are associated with increased risk for mental disorders. However, changes in Akt and GSK3 signalling are not restricted to a single disorder, and their contribution to specific behavioural symptoms or therapeutic effects may be modulated by broader changes in biologic contexts or signalling landscapes. Understanding these interactions may provide a better understanding of mental illnesses, leading to better efficacy of new therapeutic approaches.

Fig. 1

Segregation of D1 and D2 dopamine (DA) expression in the dorsal striatum. Confocal microscopy images of striatal neurons in double bacterial artificial chromosome transgenic mice expressing the green fluorescent protein reporter gene under the control of the D2 DA receptor gene promoter and the (red) tomato fluorescent protein reporter gene under the control of the DA receptor gene promoter. The arrow points to a cell that expresses both reporter genes.

Fig. 2

Signalling networks regulated by dopamine (DA) in neurons responding to D2-class agonists. Regulation of Gαs–cAMP–PKA and βArr2–Akt–GSK3 signalling by D2 receptors. The action of other neurotransmitters, growth factors and neurotrophin has been included to illustrate the role of many of these intermediates as signal integrators. Single arrows: activation. Grey lines: inhibition. Double arrows: actions that can either be activatory or inhibitory in function of specific substrates. 5-HT = serotonin; βArr2 = β-Arrestin-2; BDNF = brain-derived neurotrophic factor; cAMP = cyclic adenosine monophosphate; GPCR = G protein–coupled receptor; GSK3 = glycogen synthase kinase-3; PDK1 = 3-phosphoinositide-dependent kinase-1; Pi3K = phosphoinositide-3 kinase; PKA = protein kinase A; PP2A = protein phosphatase 2A; RTK = receptor tyrosine kinase.

Fig. 3

Model for arrestin-dependent inhibition of Akt and its regulation by lithium (Li⁺). (A) Under basal conditions, Akt phosphorylation/activation is the result of an equilibrium between activation of Akt by phosphorylation and its inactivation by protein phosphatase 2A (PP2A)–mediated dephosphorylation. Dephosphorylation of Akt is facilitated by formation of the magnesium (Mg²⁺)-dependent scaffolding of Akt and PP2A by β-Arrestin-2 (βArr2). (B) By displacing magnesium, lithium destabilizes the signalling complex formed by Akt, βArr2 and PP2A, thereby enhancing Akt activity by reducing its dephosphorylation.

Fig. 4

Regulation of Akt–GSK3 signalling by psychoactive drugs and gene products associated with mental disorders. Proteins are the product of genes associated with increased risk for schizophrenia and/or bipolar disorders. Behavioural changes in dopaminergic responses have been reported in Akt1 knockout and β-Arrestin-2 (βArr2) knockout mice and in GSK3β haploinsuficient mice. Single arrows = activation; solid lines = inhibition; double arrows = actions that can either be activatory or inhibitory in function of specific substrates. 5-HT = serotonin; BDNF = brain-derived neurotrophic factor; BMAL1 = brain and muscle Arnt-like protein-1; Clock = circadian locomotor output cycles kaput; COMT = catechol-O-methyltransferase; DA = dopamine; Disc1 = disrupted in schizophrenia 1; GSK3 = glycogen synthase kinase-3; NMDA = N-methyl-d-aspartate; NRG1 = neuregulin 1; PDK1 = 3-phosphoinositide-dependent kinase-1; Pi3K = phosphoinositide-3 kinase; PP2A = protein phosphatase 2A; TPH2 = tryptophan hydroxylase 2.