Depression is a clinically and biologically heterogeneous disease. It is one of the most prevalent and costly psychiatric disorders worldwide, with 10-30% of women and 7-15% of men likely to suffer from depression in their lifetime. Treatment for depression requires administration of antidepressant drugs for 2-6 weeks before clinical efficacy is observed. This time lag suggests that long-term adaptations in neurotransmitter systems and/or their downstream targets might be necessary for therapeutic effects. Novel hypothesis postulates that antidepressants activate not only second messenger systems leading to the activation of transcription factors such as cAMP response element-hippocampus binding protein (CREB) but also activate neurotrophic pathways and increase hippocampal neurogenesis. It is a swelling in floor of lateral ventricle of brain contains complex folding of cortical tissue and is involved with other connections of hippocampal formation, in the workings of the limbic system. Multiple classes of antidepressant drugs, including monoamine oxidase inhibitors (MAOIs), selective serotonin reuptake inhibitors (SSRIs) and selective noradrenaline reuptake inhibitors (SNRIs), increase both cell proliferation and neurogenesis in the dentate gyrus of the adult hippocampus. Gyrus is a raised convolution of the cerebral cortex between two sulci (clefts) the cellular effects occur only after chronic, and not acute, dosing, which corresponds with the therapeutic time-course for clinical efficacy of antidepressants. The challenge of pharmacological studies and animal models is to elucidate the mechanism of antidepressant action beyond neurotransmitters to identify specific intracellular second messenger pathways, determine how they impact on neurogenesis and evaluate the behavioural consequences of these cellular modifications.
Antidepressant drugs
The monoamine hypothesis of depression postulates that a functional deficiency of 5-hydroxytryptamine [5-HT (serotonin)] or noradrenaline in the brain is key to the pathology and/or behavioral manifestations associated with depression. In support of this theory, the majority of antidepressant drugs used clinically produce acute increases in the levels of 5-HT and noradrenaline. This in turn causes the activation of seven-transmembrane domain receptors that are coupled to heterotrimeric G proteins. Through G-protein activation of adenylyl cyclase, cAMP production is increased, enabling the activation of cAMP-dependent protein kinase (PKA) and phosphorylation of target proteins. Regulation of G proteins, at the level of enhanced coupling of Gs (stimulating G proteins) to adenylyl cyclase and increased adenylyl cyclase activity, occurs following antidepressant treatment. In addition, PKA activity is increased following chronic treatment of rats with either a tricycle antidepressant (imipramine), an MAOI (tranylcypromine) or electroconvulsive shock (ECS).
Although most antidepressant drugs increase intracellular levels of cAMP through activation of adrenoceptors or 5-HT receptors, it is important to note that not all subtypes of these receptors are coupled to the adenylyl cyclase-cAMP-PKA pathway. For example, activation of phospholipase C (PLC) by a1-adrenoceptors can lead to mobilization of internal Ca 2+ Cisternae stores and subsequent activation of Ca 2+ Cisternae-calmodulin (CaM) - dependent kinases. Activation of protein kinases in the cell thus enables phosphorylation of downstream effectors. One of the bestcharacterized targets for phosphorylation by a variety of kinases is the transcription factor CREB PKA and CaM kinase catalyze the transfer of phosphate from ATP to specific serine residues on this protein substrate. Activation of PKA leads to phosphorylation of a serine residue (S133) in the CREB protein that enables recruitment of co-activator proteins to initiate gene transcription. CREB is also a substrate for Ca2C - CaM kinase II and IV, which activate or inhibit CREB transactivation depending on the serine residues that are phosphorylated. In addition, mitogen, signaling through the Ras-mitogen-activated protein (MAP) kinase (MEK) - extra cellular signal-regulated protein kinase (ERK) pathway, can phosphorylate CREB via RSK2, a member of the ribosomal S6 kinase family.
Genetic models of CREB activity
Because antidepressant drugs can activate CREB, recent studies have examined whether manipulation of CREB activity and/or levels of CREB can recapitulate some effects of antidepressants. To date, the function of CREB has been investigated using animal models or viral-vectormediated gene overexpression. Given that the majority of studies have reported increased CREB and/or CREB phosphorylation after chronic antidepressant treatment, the hypothesis of many of these studies was that alterations in CREB would have effects on baseline measures in antidepressant tests.
Neurotrophins and growth factors
Several studies suggest that brain-derived nerve growth factor (BDNF) is a target of antidepressant action. Robust increases in the levels of BDNF mRNA in cortical and hippocampal regions have been reported following chronic antidepressant drug administration in rats tranylcypromine (an MAOI) and ECS increase BDNF mRNA levels BDNF has also been shown to be regulated by exposure to stress, and antidepressant treatment can block this down regulation. Furthermore, the duration of drug treatment and interval following drug administration can have an impact on the overall levels of BDNF. The BDNF binds to the trkB receptor in the brain. Upon activation by ligand-dependent autophosphorylation, this tyrosine kinase initiates a variety of intracellular signalling cascades including the MEK-ERK pathway and downstream activation of RSK2, which can phosphorylate CREB. A link between CREB and BDNF is strongly suggested by the finding that antidepressant-mediated upregulation of BDNF is blocked in CREB-deficient mice. BDNF itself produces antidepressant-like effects and might thus be one of the molecular mediators of antidepressant drugs.
Genetic models of BDNF action
Mice that lack BDNF display severe neuronal deficits and early postnatal death. However, studies examining mice that lack only one allele of the gene encoding BDNF (BDNFC/K) have identified alterations in learning and synaptic plasticity. (Synaptic plasticity is the ability of the connection or synapse between two neurons to change in strength. Some lines of BDNFC/K mice display a reduction in BDNF protein levels but without any accompanying changes in baseline behavior in models such as the FST.
Other lines of BDNFC/K mice display altered synaptic responses, but a specific behavioral phenotype associated with these alterations has not been identified. These data reveal that a partial loss of BDNF is not sufficient to affect baseline behavior but this interpretation is compromised by the fact that these animals had a loss of BDNF from birth and might have evolved compensatory responses as adults.
Insulin like growth factor
Both systemic and central administration of IGF-1 increase cell proliferation in the adult hippocampus, and IGF-1 has been shown to selectively increase maturation of neurons. Central administration of IGF-1 produces antidepressant-like effects in the forced swim tests in rats, which indicates that IGF-1 and IGF-1-induced signal transduction pathways might be another mechanism by which antidepressants exert their behavioral effects. IGF-1 stimulates the phosphoinositide 3-kinase-PKB pathway, and has been shown to phosphorylate CREB. The downstream signalling pathways of IGF-1, BDNF and even 5-HT demonstrate a high degree of overlap the functional effect of these pathways might be a combination of increasing cell proliferation and neurogenic pathways, all with the net effect of increasing synaptic strength and synaptic plasticity. Currently, there is little information available with respect to the behavioral effects of antidepressants in IGF-1 genetic models because IGF-1 mutant mice have a limited lifespan and no conditional deletions of the gene encoding IGF-1 are available.
Antidepressant-induced neurogenesis
Reduced hippocampal cell volume has been observed in depressed humans in both magnetic resonance imaging (MRI) and post-mortem studies, compared with normal individuals. Furthermore, antidepressant treatment has been shown to reverse or prevent this decrease in hippocampal volume. Multiple classes of antidepressant drugs increase both cell proliferation and neurogenesis in the dentate gyrus of the adult hippocampus, and this requires a chronic, and not an acute, time-course of administration. These findings have led to the hypothesis that antidepressant drugs might exert some of their therapeutic benefits by increasing hippocampal neurogenesis. However, a major drawback in the majority of these studies is that a causal link between the administration of antidepressants, cell proliferation or neurogenesis and antidepressant efficacy has not been demonstrated. A relationship between CREB and antidepressant induced neurogenesis is supported by the finding that the majority of antidepressants that increase neurogenesis also activate a cAMP-related second messenger pathway and increase CREB phosphorylation.
(The authors A N Nagappa, Sonal S, Upendra P S, Gitesh C N are with MCOPS, Manipal 576104; and Mayur K L is with BITS, Pilani 333031)