Brain-derived neurotrophic factor (BDNF) is one of a series of peptide growth factors secreted from neurons and having its own specific receptor. Nerve growth factor (NGF) has TRKA as its receptor, BDNF has TRKB, and neurotrophic factor 3 (NT-3) acts at the TRKC receptor. These neurotrophic factors appear to have different functions at different stages of neurogenesis and development.
It appears that they are crucial for the initial neuronal and synaptic connectivity of the central nervous system (CNS), during which cells that "fire together, wire together." At this stage of development, many of the neurotrophic factors are secreted by the cell bodies of the stimulated (postsynaptic) neurons, picked up by axon terminals, and retro-gradely transported back to the nucleus of the innervating neuron; in this manner they alter the patterns of gene expression for maintenance of synaptic efficacy and even neuronal survival. In addition to a role in the basic wiring diagram of the CNS, it would appear that they are also involved in a more subtle sculpting and resculpting of the CNS based on experience-dependent neural plasticity.
In the adult animal, BDNF appears to be integrally involved in long-term potentiation and other models of learning and memory. For example, in genetically modified mice in which BDNF is knocked out, long-term potentiation fails. This failure appears to be physiologically and functionally relevant to the animal because it is unable to navigate based on spatial cues to find a previously discovered submerged platform in the Morris water maze test.
Although it has not been definitively demonstrated, considerable new evidence suggests that BDNF and related neurotrophic factors may be released in a feed-forward fashion with neuronal firing, rather than simply having up take and retrograde transfer back to the innervating neuron. This is potentially of considerable interest in the dentate granule cells of the hippocampus, which not only are involved in the trisynaptic glutamate-based excitatory circuitry important for learning and memory, but also are capable of producing (and likely releasing) BDNF from their presynaptic terminals.
In the amygdala kindling paradigm wherein repeated subthreshold stimulations of the amygdala eventually come to evoke full-blown tonic-clonic seizures, the dentate granule cells show dendritic sprouting as well as axonal sprouting onto the CA3 pyramidal cells. While kindling induces increases in BDNF mRNA expression, stresses decrease in the same area of the dentate granule cells of the hippocampus.
There is some specificity of the effects on BDNF as a function of both anatomical area involved and specific type of neurotrophic factor. Thus, although stress decreases BDNF in the hippocampus, it increases NT-3, and the effects on BDNF are in the opposite direction in the hypothalamic-pituitary-adrenal axis, which hypothetically could contribute to the increased size of the pituitary and adrenal glands in patients with major depression.
In neonatal rat pups, 24 hours of maternal deprivation results in substantial decrements in BDNF in the hippocampus and a doubling in the rate of the diffuse neuronal apoptosis that occurs in the 12-day-old animal. Repeated experiences of maternal deprivation for 3 hours in the first 10 days of life result in an animal that is permanently hyperactive and hypercortisolemic, as well as prone to alcohol and cocaine self-administration as compared with its non-deprived litter mates. These biochemical and behavioral defects are reversed by chronic treatment with serotonin-selective antidepressants but return when these treatments are discontinued. While alterations in BDNF or other neurotrophic factors have not been definitively linked to these long-term biochemical and behavioral changes in this psychosocial stressor paradigm, they provide a plausible mechanism.
The potential bidirectionality of such experiential effects is further emphasized by the work of Meaney and colleagues, who observed that 15 minutes of maternal deprivation resulted in increased maternal attention and licking upon reunion and subsequently thereafter, and thus engendered protective effects against stress-related hyper-cortisolemia and even age-related decline in hippocampal structure and memory loss. Parallel effects were observed in the offspring of mothers who were high natural lickers of their infants compared with those who naturally engaged in lesser degrees of this grooming and contact behavior.
Many of the currently utilized psychotropic agents have effects on neurotrophic factor gene expression, including that of BDNF. Smith and colleagues were the first to demonstrate the opposite effects of stress and antidepres-sants on BDNF mRNAin the hippocampus; these data were replicated and extended by Duman and colleagues at Yale.
They found that antidepressants as a class, including electroconvulsive therapy, increase BDNF gene expression following chronic administration. Moreover, there is partial amelioration of some of the stress-induced decrements in BDNF gene expression if antidepressants are used prior to or concurrently with the stress induction.
From the clinical perspective, this raises the potential of different types of benefit from long-term antidepressant prophylaxis in individuals with recurrent unipolar depression. They prevent recurrent depression, and to the extent that the preclinical data in animals are relevant to the human condition—and some preliminary autopsy data from the Stanley Foundation brain collection are at least consistent with this perspective—it is possible that antidepressants could be partially protective to the effects of stressors on BDNF gene expression. This might be useful and neu-roprotective in its own right, but to the extent that some types of stressors are involved in the triggering of affective episodes, this could be involved in depression prophylaxis.
Preliminary evidence also suggests that BDNF is positive in some animal paradigms predictive of the efficacy of antidepressants, further raising the speculation that more direct targeting of BDNF specifically for therapeutic purposes, either by increasing BDNF itself or increasing activity at its TRKB receptor, may ultimately provide a new approach to the therapeutics of depression, possibly at a level of primary as well as secondary prevention.
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