title: NMDA receptor dysregulation in chronic state: a possible mechanism underlying depression with BDNF downregulation.
abstract: Several lines of evidence indicate that chronic stress and downregulation of brain-derived neurotrophic factor (BNDF) are the key components of depression pathology. Evidence from animal models of depression demonstrates that chronic stress impairs hippocampal BDNF expression and that antidepressant drug effects correlate with increased BDNF synthesis and activity in the hippocampus. Studies with human carriers of BDNF Met-allele polymorphism link stress vulnerability and risk for depression. The mechanism by which chronic stress downregulates BDNF and promotes depressive-like responses is not established yet. It has been reported that chronic stress mediates alterations in several calcium-related components involved in BDNF synthesis, including CAMKII, CAMKIV and cAMP-response element-binding protein (CREB), and glutamatergic neurotransmission through N-Methyl-D-Aspartate receptors (NMDAR). Treatments with NMDAR antagonists like ketamine modulate glutamate signals, upregulate CREB and BDNF expression, and correct stress-induced cognitive and behavioral alterations. With the increasing interest to develop NMDAR modulators, it is crucial to understand the conditions that lead to depression pathology in order to develop rational therapies aimed at reestablishing proper neuronal function. We present here the current knowledge regarding the relation between chronic stress, BDNF and NMDARs and its implications in depression. We discuss a plausible mechanism where chronic stress induced NMDAR stimulation could lead to dysregulated calcium signaling and decreased BDNF activity. In these circumstances, neurons become vulnerable to the effects of stress, leading to dysfunctional neurotransmission and behavioral alterations. We propose that treatment with NMDAR antagonists may help to return the balance of calcium signaling, promote proper BDNF signaling and correct depressive symptoms.
authors.affiliation: Center for Neuroscience, INDICASAT AIP, Ciudad del Saber, Edificio #219, Apartado Postal 0843-01103, Panamá, República de Panamá; Department of Biotechnology, Acharya Nagarjuna University, Nagarjuna Nagar, Guntur 522510, India. Electronic address: cvasquez@indicasat.org.pa.
authors.forename: Carol E
authors.initials: CE
authors.lastname: Vásquez
authors.affiliation: Department of Biotechnology, University of Santa Cruz, California, 1156 High St, Santa Cruz, CA 95064, USA.
authors.forename: Romina
authors.initials: R
authors.lastname: Riener
authors.affiliation: Biology Department, 111 Kunkel Hall, Lafayette College, Easton, Pennsylvania 18042, USA.
authors.forename: Elaine
authors.initials: E
authors.lastname: Reynolds
authors.affiliation: Center for Neuroscience, INDICASAT AIP, Ciudad del Saber, Edificio #219, Apartado Postal 0843-01103, Panamá, República de Panamá
authors.forename: Gabrielle B
authors.initials: GB
authors.lastname: Britton
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000096:biosynthesis / Q000235:genetics*; D003863:Depression / Q000378:metabolism* / Q000523:psychology; D015536:Down-Regulation; D044127:Epigenesis, Genetic; D006801:Humans; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D013315:Stress, Psychological / Q000378:metabolism / Q000523:psychology
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D016194:Receptors, N-Methyl-D-Aspartate
keywords: Calcium signaling; Glutamate; Hippocampus; Psychological; Stress