Connexin 43: insights into candidate pathological mechanisms of depression and its implications in antidepressant therapy

Abstract

Major depressive disorder (MDD), a chronic and recurrent disease characterized by anhedonia, pessimism or even suicidal thought, remains a major chronic mental concern worldwide. Connexin 43 (Cx43) is the most abundant connexin expressed in astrocytes and forms the gap junction channels (GJCs) between astrocytes, the most abundant and functional glial cells in the brain. Astrocytes regulate neurons' synaptic strength and function by expressing receptors and regulating various neurotransmitters. Astrocyte dysfunction causes synaptic abnormalities, which are related to various mood disorders, e.g., depression. Increasing evidence suggests a crucial role of Cx43 in the pathogenesis of depression. Depression down-regulates Cx43 expression in humans and rats, and dysfunction of Cx43 also induces depressive behaviors in rats and mice. Recently Cx43 has received considerable critical attention and is highly implicated in the onset of depression. However, the pathological mechanisms of depression-like behavior associated with Cx43 still remain ambiguous. In this review we summarize the recent progress regarding the underlying mechanisms of Cx43 in the etiology of depression-like behaviors including gliotransmission, metabolic disorders, and neuroinflammation. We also discuss the effects of antidepressants (monoamine antidepressants and ketamine) on Cx43. The clarity of the candidate pathological mechanisms of depression-like behaviors associated with Cx43 and its potential pharmacological roles for antidepressants will benefit the exploration of a novel antidepressant target.

Keywords: ATP; Ca2+ wave; Connexin 43; antidepressant target; astrocyte; depression; hippocampus; prefrontal cortex.

Fig. 1. Cx43 and glutamate-glutamine cycle under physiological conditions.

Under physiological conditions, the function of Cx43 GJCs is normal, and most of the HCs remain closed. Presynaptic neurons release glutamate through vesicles. Glutamate in the synaptic cleft binds to the glutamate receptors on postsynaptic neurons, including NMDAR and AMPAR. Then, glutamate is quickly removed from the synaptic cleft, and more than 90% is taken up by astrocytes via the astrocyte-specific glutamate transporter GLT-1. In astrocytes, glutamate is converted to glutamine by glial-specific glutamine synthetase. A part of glutamine shuttles back to the presynaptic neurons. It is converted into glutamate by neuron-specific phosphoric acid-activated glutaminase to supplement and maintain the glutamate storage of the presynaptic neurons. Also, a part of glutamine enters GABAergic interneurons to synthesize GABA, binding to GABAR on presynaptic neurons and inhibiting glutamate release. Through the above two aspects of regulation, the concentration of glutamate in the synaptic cleft keeps low. AMPAR a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, GABA γ-aminobutyric acid, GJC gap junction channel, GLT-1 glutamate transporter 1, HC hemichannels, NMDAR N-methyl-D-aspartate-receptor.

Fig. 2. Cx43 and glutamate-glutamine cycle under stress conditions.

(1) Stress causes dysfunction of Cx43 GJCs and activation of Cx43 HCs. (2) Dysfunction of GJCs reduces the expression of GLT-1. A possible intermediate target is GFAP. The activated HCs release large amounts of glutamate into the synaptic cleft. (3) The clearance of glutamate through GLT-1 decreases, and glutamine synthesis in astrocytes decreases. (4) Glutamine shuttled back to the presynaptic neurons decreases, and glutamate storage of presynaptic neurons decreases. (5) Glutamine entering into GABAergic interneurons decreases, and the synthesis of GABA reduces. The inhibitory effect of GABAergic neurons on the release of glutamate from presynaptic neurons is weakened. (6) Reduced glutamate clearance by GLT-1, increased release of glutamate by HCs, and dysfunction of GABAergic system together leads to the accumulation of glutamate in the synaptic cleft. Accumulated glutamate in the synaptic cleft leads to excessive and continuous activation of NMDAR and AMPAR, resulting in a decrease of BDNF release, thereby contributing to the onset of depression. AMPAR a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, BDNF brain-derived neurotrophic factor, GABA γ-aminobutyric acid, GFAP glial fibrillary acidic protein, GJC gap junction channel, GLT-1 glutamate transporter 1, HC hemichannels, NMDAR N-methyl-D-aspartate-receptor.

Fig. 3. Under stress conditions, ATP mediates the formation of ICWs through Cx43 GJCs and HCs.

(1) Glutamatergic signaling triggers Ca²⁺ influx into neurons through AMPAR or NMDAR, resulting in a localized decrease in the extracellular Ca²⁺ concentration. (2) Cx43 HCs in astrocytes open in response to low extracellular Ca²⁺ conditions and mediate the efflux of ATP. (3) ATP binds to P₂YRs on astrocytes and then activates G protein and PLC, promoting the release of intracellular IP₃. (4) The combination of IP₃ and IP₃R on the ER membrane causes calcium release from ER, forming calcium waves. (5) Calcium waves regulate the release of neurotransmitters from presynaptic neurons and further promote the release of ATP from HCs. (6) ATP is degraded to ADP. ADP activates interneuronal P₂Y1 receptors, stimulating depolarization and firing, thereby enhancing inhibitory transmission. (7) ICWs transmit through Cx43 GJCs and HCs. Both Ca²⁺ and IP₃ can enter the cytoplasm of adjacent astrocytes through GJCs and then induce the calcium waves in adjacent astrocytes. ATP released from HCs activates P₂YRs on the membrane of neighboring cells and then induces the release of IP₃ and subsequent calcium release from the ER calcium stores. (8) A large-scale calcium wave is formed in the astrocyte network to regulate neuronal activities under stress conditions. ADP adenosine diphosphate, AMPAR a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor, ATP adenosine triphosphate, ER endoplasmic reticulum, GJC gap junction channel, HC hemichannels, ICW intercellular calcium waves, IP₃ inositol triphosphate, NMDAR N-methyl-D-aspartate-receptor, PLC phospholipase C.

Fig. 4. Cx43 dysfunction contributes to depression through peripheral mechanisms.

(1) ERS in hepatocytes spreads through Cx43 GJCs and promotes insulin resistance. (2) Insulin resistance causes Cx43 GJC dysfunction by increasing the level of H₂O₂ in vascular smooth muscle cells. (3) TSH promotes TH production by increasing the synthesis of Cx43 and inducing the opening of Cx43 GJCs in thyrocytes. (4) Excessive CORT produced by adrenocortical cells causes Cx43 GJC dysfunction of astrocytes in the brain. (5) Under conditions of stress, activated microglia releases inflammatory factors, promoting Cx43 HC opening and Cx43 GJC dysfuntion of astrocytes. (6) Opened HCs further contribute to the activation and spread of the inflammasome pathway. (7) Insulin resistance can promote neuroinflammation and affect the brain function. CORT corticosterone, ERS endoplasmic reticulum stress, GJCs gap junction channels, HC hemichannel, TH thyroid hormone, TSH thyroid stimulating hormone.