ReviewActivation of Mammalian Target of Rapamycin and Synaptogenesis: Role in the Actions of Rapid-Acting Antidepressants
Section snippets
Chronic Stress Produces Neuronal Atrophy and Maladaptive Impairments of Neuroplasticity
Theories of depression suggest that exposure to chronic stress and the neuronal changes that follow produce susceptibility to mood disorders by impairing synaptic number and function 4, 5, 6. Studies of postmortem human tissue report decreases in neuronal size in the dorsolateral PFC (7), anterior cingulate cortex 8, 9, orbitofrontal cortex 10, 11, 12, and hippocampus (13). Alterations in glial density in the PFC and hippocampus have also been observed 7, 9, 12. A recent electron microscopy
mTOR Regulates Protein Translation and Synaptic Plasticity
The mTOR complex is a ubiquitously expressed and integrates signals from neuronal activity, growth factors, energy, and nutrient levels to regulate rates of protein translation and synaptic plasticity as well as other cellular functions. There are two mTOR complexes known as mTORC1 and mTORC2, which are comprised of the mTOR serine/threonine protein kinase bound to distinct accessory proteins Raptor and Rictor, respectively, and have different substrates (for an extensive review of mTOR
Aberrant mTOR Signaling Is Observed in Neurological and Psychiatric Disorders
A large body of evidence implicates mTOR dysregulation in the etiology of various neurological and psychiatric disorders (39). For example, mTOR signaling is increased in Alzheimer’s disease (40) and is involved in learning deficits observed in tuberous sclerosis (38). The mTOR cascade is altered in patients with fragile X syndrome (41), an autism spectrum disorder that is caused by the silencing of the FMR1 gene (42). The product of FMR1 is the mRNA binding protein fragile X mental retardation
NMDA Receptor Antagonists Activate mTOR Signaling, Produce mTOR-Dependent Behavioral Responses, and Rapidly Reverse the Effects of Stress
Ketamine produces rapid and acute antidepressant-like effects in the rodent forced swim and learned helplessness tests 49, 50, 51. Similarly, in nonstressed, naïve rats, systemic treatment with ketamine rapidly increases levels of synaptic proteins (i.e., GluR1, PSD95) and the number and function of excitatory glutamatergic synapses in the PFC (51). Biochemical studies have discovered that ketamine rapidly activates signaling through the mTOR pathway as well as downstream substrates of mTOR
BDNF Is Required for the Actions of Ketamine
Reduced BDNF expression and signaling have long been linked to actions of stress, and conversely induction of this factor has been implicated in the response to antidepressants. Electroconvulsive shock and chronic antidepressants increase BDNF expression in the hippocampus and PFC (67). Furthermore, infusion of BDNF is sufficient to produce antidepressant-like effects in rodents 68, 69.
Recent studies have demonstrated the importance of BDNF signaling in the rapid antidepressant effects of
GSK-3 and Inhibition of Long-Term Depression
Glycogen synthase kinase 3 is important for regulating gene expression and synaptic plasticity and is thought to play an important role in depression as well as other psychiatric illnesses such as schizophrenia (76). Genetic analyses suggest that SNPs in the GSK-3β gene are associated with occurrence of depression and structural brain changes 77, 78. Glycogen synthase kinase 3 acts on numerous downstream effectors, including TSC1/2. Phosphorylation of TSC2 by GSK-3 enhances the suppression of
Novel Targets for Rapid-Acting Antidepressants
There is an unmet need for novel antidepressant agents that produce more efficacious and rapid antidepressant actions. Recent studies have demonstrated that putative rapid-acting antidepressants might share the ability of ketamine to increase mTOR signaling and for rapid reversal of the effects of stress. Some of these mechanisms are discussed in the following text and shown in Figure 2.
Summary and Conclusions
The discovery that ketamine produces rapid and efficacious antidepressant responses in treatment-resistant patients has had a profound impact on research to understand and develop additional rapid-acting agents. Unlike typical antidepressants, ketamine has the unique ability to rapidly reverse the neuronal deficits and impaired plasticity produced by chronic stress. The mTOR pathway plays a critical role in these effects by activating synaptic translational machinery and increasing mature
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