Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections

Abstract

Despite the complexity and heterogeneity of mood disorders, basic and clinical research studies have begun to elucidate the pathophysiology of depression and to identify rapid, efficacious antidepressant agents. Stress and depression are associated with neuronal atrophy, characterized by loss of synaptic connections in key cortical and limbic brain regions implicated in depression. This is thought to occur in part via decreased expression and function of growth factors, such as brain-derived neurotrophic factor (BDNF), in the prefrontal cortex (PFC) and hippocampus. These structural alterations are difficult to reverse with typical antidepressants. However, recent studies demonstrate that ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist that produces rapid antidepressant actions in treatment-resistant depressed patients, rapidly increases spine synapses in the PFC and reverses the deficits caused by chronic stress. This is thought to occur by disinhibition of glutamate transmission, resulting in a rapid but transient burst of glutamate, followed by an increase in BDNF release and activation of downstream signaling pathways that stimulate synapse formation. Recent work demonstrates that the rapid-acting antidepressant effects of scopolamine, a muscarinic receptor antagonist, are also associated with increased glutamate transmission and synapse formation. These findings have resulted in testing and identification of additional targets and agents that influence glutamate transmission and have rapid antidepressant actions in rodent models and in clinical trials. Together these studies have created tremendous excitement and hope for a new generation of rapid, efficacious antidepressants.

Keywords: BDNF; glutamate; ketamine; mTORC1; prefrontal cortex; rapamycin; scopolamine; stress; synaptogenesis.

Figure 1.. Chronic stress causes neuronal atrophy: a decreased number of spine synapses. Basic research studies demonstrate that repeated stress causes atrophy of neurons in the prefrontal cortex and hippocampus of rodents. Shown on the left is a diagram of a segment of a dendrite that is decorated with spines, and the reduction in spine number after exposure to repeated stress. On the right are examples of two photon laser microscopy images of neurobiotin-labeled dendrites from layer V pyramidal neurons in the prefrontal cortex of rats housed under control conditions or after exposure to immobilization stress (7 days, 45 minutes per day).

Figure 2.. Stress and depression decrease, while rapid-acting antidepressants (eg, ketamine) increase, synaptic connections. Under normal, nonstress conditions, synapses of glutamate terminals are maintained and regulated by circuit activity and function, including activity-dependent release of brain derived neurotrophic factor (BDNF) and downstream signaling pathways. Stress and depression are associated with neuronal atrophy and decreased synaptic connections in the prefrontal cortex and hippocampus. This is thought to occur via decreased expression and release of BDNF as well as increased levels of adrenal glucocorticoids. This decrease has been compared with long-term depression (LTD). Rapid-acting antidepressants, notably ketamine, cause a burst of glutamate that results in an increase in synaptogenesis that has been compared with long-term potentiation (LTP). The increase in glutamate is thought to occur via blockade of N-methyl-Daspartate (NMDA) receptors located on inhibitory γ-aminobutyric acid (GABA)--ergic neurons, resulting in disinhibition of glutamate transmission. The burst of glutamate increases BDNF release and causes activation of mammalian target of rapamycin (mTOR) signaling, which then increases the synthesis of synaptic proteins required for new spine synapse formation. These new connections allow for proper circuit activity and normal control of mood and emotion. However, the new synapses are unstable and are lost after about 10 days, which coincides with depression relapse in patients. Akt, protein kinase b; AMPA, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionicacid; ERK, extracellular signal-regulated kinases; GABA, γ-aminobutyric acid; GSK, glycogen synthase kinase; PP1, phosphoprotein phosphatase 1; TrkB, tropomyosin receptor kinase B

Figure 3.. Glutamatergic targets for rapid-acting antidepressants. Basic research studies demonstrate that ketamine causes a rapid and transient burst of glutamate in the prefrontal cortex, in part via disinhibition of γ-aminobutyric acid (GABA)-ergic neurons that exert negative control over glutamatergic firing. Recent basic and clinical studies have demonstrated a number of related glutamatergic, as well as muscarinic, cholinergic targets with the potential to produce rapid-acting antidepressant effects. In addition to ketamine, the nonselective Nmethyl-D-aspartate (NMDA) antagonist AZD6765 and the selective NR2b antagonists CP-101,606 and Ro 25-6981 have shown efficacy in clinical trials and/or rodent models. A highly novel tetrapeptide, GLYX-13, which is a partial agonist/antagonist at the glycine binding site on the NMDA receptor also produces rapid antidepressant responses in rodents and in clinical trials. The metabotropic glutamate receptor 2/3 (mGluR2/3) antagonists LY341495 and MGS0039 have also been shown to increase glutamate and produce rapid, mammalian target of rapamycin (mTOR)-dependent antidepressant effects in rodent models. The nonselective muscarinic receptor antagonist scopolamine, as well as telenzapine, which has modest M1 selectivity, also increase glutamate and produce rapid mTOR-dependent antidepressant effects. It is important to point out that these agents may also act at postsynaptic sites to enhance synapse formation and produce antidepressant responses. Also acting at postsynaptic sites are α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor potentiating agents, although studies are still underway to determine the efficacy of these agents as rapid-acting drugs in rodent models. Inhibition of GSK3 contributes to the actions of ketamine, and the nonselective GSK3 antagonist lithium and selective agent SB216763 enhance the behavioral and synaptic responses to ketamine. Akt, protein kinase b; ERK, extracellular signal-regulated kinases; GABA, γ-aminobutyric acid; GSK, glycogen synthase kinase; PP1, phosphoprotein phosphatase 1 ; TrkB, tropomyosin receptor kinase B