Synaptic plasticity and depression: new insights from stress and rapid-acting antidepressants

Abstract

Depression is a common, devastating illness. Current pharmacotherapies help many patients, but high rates of a partial response or no response, and the delayed onset of the effects of antidepressant therapies, leave many patients inadequately treated. However, new insights into the neurobiology of stress and human mood disorders have shed light on mechanisms underlying the vulnerability of individuals to depression and have pointed to novel antidepressants. Environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology, resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function. Although current antidepressants, such as serotonin-reuptake inhibitors, produce subtle changes that take effect in weeks or months, it has recently been shown that treatment with new agents results in an improvement in mood ratings within hours of dosing patients who are resistant to typical antidepressants. Within a similar time scale, these new agents have also been shown to reverse the synaptic deficits caused by stress.

Figures

Figure 1. Heterogeneity of depression and influences on susceptibility to depression

The heterogeneity of depression results from one or more pathological determinants. Notable effects include stress on brain neurotransmitter systems (NTs),activation of the HPA axis and cortisol, the innate immune system and inflammatory cytokines, fluctuations of ovarian steroids, the gastro intestinal (GI) system, adipose tissue and related peptides and microbiome, the cardiovascular system (e.g., VEGF or vascular endothelial growth factor), and gene polymorphisms that influence vulnerability and other organ systems as shown. These systems lead to increased incidence of depression as well as comorbid illnesses.

Figure 2. Chronic stress causes atrophy of neuronal processes and decreases synapse number

(a) The influence of repeated restraint stress (7 d) on pyramidal neurons (layer V) in the medial prefrontal cortex (mPFC) of rat. Pyramidal neurons in sections of mPFC are visualized after filling with neurobiotin and two-photon laser scanning microscopy. The left panels show the effects of repeated stress on the entire reconstructed pyramidal neurons, demonstrating a reduction in the number and length of apical dendrites. The higher power images on the right show a segment of dendrite decorated with spines (arrows), the point of synaptic contacts with neuronal inputs to the mPFC; repeated stress significantly decreases the number and function (determined electrophysiologically) of spine synapses. The lower panel shows the signaling pathways that lead to decreased numbers of synapses in response to stress, including decreased BDNF and mTORC1 signaling. Under normal conditions the upon stimulation the excitatory synapse releases glutamate and resulting in activation of postsynaptic glutamate AMPA receptors and depolarization; this causes activation of multiple intracellular pathways, including BDNF-TrkB signaling (and the downstream kinases Akt and ERK) and activation of the mTORC1 pathway. These pathways are essential for regulation of synaptic plasticity, a fundamental adaptive learning mechanism that includes maturation (increased spine head diameter) and number of synapses. This process requires mTORC1 mediated new protein synthesis of synaptic proteins, including glutamate GluA1 AMPA receptors and postsynaptic density protein PSD95. Repeated stress decreases BDNF and mTORC1 signaling in part via up-regulation of the negative regulator REDD1 (regulated in DNA damage and repair), which decreases the synthesis of synaptic proteins and thereby contributes to decreased number of spine synapses. Other pathways involved in the regulation of synaptic plasticity are GSK3 (glycogen synthase kinase 3) and PP1 (protein phosphatase 1).

Figure 3. The multiple heterogeneous signaling pathways that influence synapse formation and stability and that could contribute to loss of synapses in depression

This includes neurotransmitters (i.e., glutamate), growth factors/neurotrophic factors (GFs/NTFs, cytokines (e.g., tumor necrosis factor α, TNFα), energy and metabolic factors (ATP, amino acids), sex steroids (e.g., estrogen), and the HPA axis (the glucocorticoid cortisol). These systems influence multiple intracellular signaling cascades that regulate all aspects of neuronal function. One of the key pathways of interest is the mTORC1 signaling cascade, which is a sensor of synaptic activity and multiple systems that can influence synaptic protein synthesis and plasticity as shown. Activation of mTORC1 signaling can occur via regulation of phosphatidylinositide 3 kinase (PI3K) and stimulation of protein kinase B (Akt). PI3K can be directly or indirectly (via multiple steps) stimulated by the different factors indicated, notably glutamate (via AMPA or mGlu receptors), estrogen (via estrogen receptors), BDNF, and other neurotrophins and growth factors. Stress and glucocorticoids via the glucocorticoid receptor (GR) can inhibit mTORC1 signaling via induction of factors that inhibit mTORC1 stability. Metabolic factors including ATP and amino acids that are required for protein synthesis, can also regulate mTORC1. Activation mTORC1 signaling leads to increased synthesis of proteins (e.g., GluA1 and PSD95) required for the maturation of existing synapses and formation of new ones. The insertion of GluA1 is also a point of regulation, notably by glycogen synthase kinase 3 (GSK3), and is involved in cellular models of learning and memory (i.e., LTP, long term potentiation; and LTD, long term depression).

Figure 4. Mechansisms of action of the fast acting antidepressant ketamine in the medial prefrontal cortex

Ketamine causes a burst of glutamate that is thought to occur via disinhibition of GABA interneurons; the tonic firing of these GABA interneurons is driven by NMDA receptors, and the active, open channel state allows ketamine to enter and block channel activity. The resulting glutamate burst stimulates AMPA receptors causing depolarization and activation of voltage dependent Ca2+ channels, leading to release of BDNF and stimulation of TrkB-Akt that activates mTORC1 signaling leading to increased synthesis of proteins required for synapse maturation and formation (i.e., GluA1 and PSD95). Under conditions where BDNF release is blocked (BDNF Met knockin mice) or neutralized (BDNF neutralizing antibody) or when mTORC1 signaling is blocked (rapamycin infusion into the mPFC) the synaptic and behavioral actions of ketamine are blocked. Scopolamine also causes a glutamate burst via blockade of acetylcholine muscarinic M1 (ACh-M1) receptors on GABA interneurons. Antagonists of glutamate metabotropic 2/3 receptors (mGluR2/3) also produce rapid antidepressant actions via blockade of presynaptic autoreceptors that inhibit the release of glutamate. Relapse to a depressive state is associated with reduction of synapses on mPFC neurons, which could occur via stress and imbalance of endocrine (cortisol), estrogen, inflammatory cytokines, metabolic, and cardiovascular illnesses.