Information about the pathophysiology of psychiatric disorders is important in developing better therapeutic approaches for the treatment of mental illness. Evidence over the past several years has suggested that deficits in the expression of brain-derived neurotrophic factor (BDNF) may contribute to the pathophysiology of a variety of -psychiatric disorders, including depression, bipolar disorder, and schizophrenia, as well as a number of neurodegenerative disorders such as Alzheimer's, Huntington's, and Parkinson's diseases (1—3). These findings have set off a flurry of activity aimed at -elucidating of the role of BDNF in these disease processes as well as in developing strategies to examine whether increasing levels of BDNF can improve clinical outcomes.

BDNF is a member of the protein family of neurotrophic factors that are important for growth, differentiation, and survival of neurons. BDNF binds with high affinity to the TrkB receptor that then activates intracellular signaling pathways that ultimately affect neuronal function. Preclinical, clinical, and postmortem studies have identified lower levels of BDNF expression in a variety of psychiatric and neurodegenerative disorders (1—3). Not surprisingly, deficits in the BDNF-TrkB signaling pathway have also been identified in many of these same disorders, suggesting that activation of this pathway may be a viable therapeutic target.

One way to activate the TrkB pathway is to increase BDNF levels. Therapeutic strategies in which exogenous BDNF is administered would seem to be a straightforward approach, but there are caveats. Oral or systemic administration of BDNF has proven unfeasible, since this protein would be broken down by digestive enzymes and cannot cross the blood-brain barrier. Intracerebroventricular infusion of BDNF protein is a possible way to augment neurotrophin signaling in the disease state, but the invasive nature of the approach may prove problematic. Another strategy is delivery of BDNF by gene therapy, but the ability to control the amount of BDNF production in the long term as well as in a cell-specific manner may prove difficult to achieve. Research is also focused on drugs that increase endogenous expression of BDNF, examples of which include antidepressants and ampakines, which have additional action in the brain.

Another method of activating the BDNF-TrkB signaling pathway is to develop a BDNF mimetic that could bind to TrkB and trigger activation of the downstream signaling pathway. The identification of small molecules that are able to bind and activate TrkB would represent a novel and exciting approach that would bypass the concerns associated with increasing BDNF levels per se and could have utility for a variety of disorders. Recent work has suggested that the use of small molecules to activate TrkB may be a viable tool for the study of this receptor signaling pathway as well as a potential therapeutic strategy for a number of brain disorders (4, 5).

The study by Andero and colleagues reported in this issue (6) examines the effect of a recently discovered small-molecule agonist of TrkB receptors on emotional learning. The compound, 7,8-dihydroxyflavone (7,8-DHF), was identified in a chemical screen of small molecules as a selective TrkB receptor agonist in vitro (5). A subsequent study (7) showed that this compound, when administered systemically in rodents, is neuroprotective and rescues BDNF deficits in a mouse model with reduced BDNF expression. Andero et al. administered 7,8-DHF systemically to rodents and found activation of TrkB receptors in the amygdala and enhanced acquisition of conditioned fear. Moreover, administration of 7,8-DHF was shown to enhance extinction of conditioned fear, a BDNF-dependent process. Deficits in extinction of conditioned fear have been suggested to underlie aspects of fear-based pathophysiology, such as posttraumatic stress disorder (8, 9). Andero et al. go on to show that 7,8-DHF enhances extinction of conditioned fear in mice that had previously been stressed. The ability of 7,8-DHF to enhance extinction of conditioned fear in naive animals—and, more importantly, in stressed animals in which extinction deficits may underlie the response—is provocative and could have important implications for the treatment of fear and stress disorders.

The approach of using small molecules to mimic growth factors represents an exciting avenue for exploring the therapeutic utility of TrkB activation for a variety of disorders. However, some caution should be used when using strategies to augment TrkB activation. In earlier preclinical studies, transgenic mice that overexpress BDNF showed some deleterious effects in the CNS, including impaired learning and memory and alterations in synaptic plasticity (10). These results suggest that too much BDNF, which would result in heightened TrkB activation, can be problematic. While one could argue that this risk would be reduced given that these TrkB agonists are intended for use in diseases in which BDNF expression is believed to be inherently deficient, it is likely that patients would receive treatment with these small molecules over extended periods. Thus, it will be necessary to ensure that therapeutic approaches using small molecules such as 7,8-DHF result in a specific range of TrkB activation without producing adverse effects.

The identification of small molecules such as 7,8-DHF represents a promising avenue for exploring the role of TrkB activation in learning and memory as well as other processes. The study by Andero et al. advances our understanding of this specific signaling pathway in extinction learning in the amygdala as well as the potential utility of small molecules such as 7,8-DHF for the treatment of stress disorders. While there is still much work to be done to investigate their safety and efficacy, these small-molecule agonists of TrkB may have important implications for the future treatment of neurodegenerative and psychiatric disorders.