Targets of polyamine dysregulation in major depression and suicide: Activity-dependent feedback, excitability, and neurotransmission

Abstract

Major depressive disorder (MDD) is a leading cause of disability worldwide characterized by altered neuronal activity in brain regions involved in the control of stress and emotion. Although multiple lines of evidence suggest that altered stress-coping mechanisms underlie the etiology of MDD, the homeostatic control of neuronal excitability in MDD at the molecular level is not well established. In this review, we examine past and current evidence implicating dysregulation of the polyamine system as a central factor in the homeostatic response to stress and the etiology of MDD. We discuss the cellular effects of abnormal metabolism of polyamines in the context of their role in sensing and modulation of neuronal, electrical, and synaptic activity. Finally, we discuss evidence supporting an allostatic model of depression based on a chronic elevation in polyamine levels resulting in self-sustained stress response mechanisms maintained by maladaptive homeostatic mechanisms.

Keywords: Excitability; Homeostasis; Ion channels; Major depression; Neurotransmitter receptors; Polyamine system; Suicide.

Figure 1. Chemical structure of positively charged polyamines in solution

Figure 2. Polyamine metabolism and potential induction pathways in neurons

Membrane proteins that permeate Ca²⁺ during cellular activity induce ODC activity and increases cytosolic polyamine concentration. Although It is not known if Ca²⁺ can directly induce ODC activity there are two alternative pathways that are known to induce ODC activity in cardiac cells. The activity of ODC is negatively regulated by antizyme and the concentration of polyamines are controlled by anabolic (green boxes) and catabolic (red boxes) enzymes. NMDAR, NMDA-type glutamate receptor; nAChR, nicotinic acetylcholine receptor; AMPAR, AMPA-type glutamate receptor; VGCC, voltage-gated Ca²⁺ channels; P42/P44 MAPK, P42/P44 mitogen-activated protein kinase signaling; P13K/AKt, phosphoinositide 3-kinase/Protein kinase B signaling; ODC, L-ornithine decarboxylase; AMD1, S-adenosylmethionine decarboxylase; SRM, Spermidine synthase; SMS spermine synthase; SMO, spermine oxidase; SAT1, spermidine/spermine-N1-acetyltransferase; PAOX, acetylpolyamine oxidase.

Figure 3. Polyamine system interdependence with fundamental properties of neuronal electrical activity

Each box indicates the membrane protein targets (in bold) that are modulated by cytosolic or extracellular polyamines. More information about the specific type of modulation is found in table 1.

Figure 4. Polyamine dysregulation in MDD

In health a balanced polyamine metabolism (represented by the ratio ODC1/SAT1 = 1) will provide a concentration of polyamines required for the normal modulation of cationic receptors and channels. Abnormal polyamine metabolic ratio, due to ODC1 overactivity or SAT1 deficits, may produce a long term increase in polyamines concentrations that saturates its “excitability buffer” capacity and lead to hyperexcitation. Excess of polyamines may increase the efflux of polyamine and potentiate excitatory synapses through sensitization of NMDAB, ASIC1a, nicotinic and TRPV receptors that are highly expressed in brain regions involved in emotion and stress control, and are positively modulated by polyamines. Long term stress-driven and polyamine-enabled excitation may lead to remodeling of neuronal properties that underlies the hyperexcitability and hyper-reactivity found in MDD.