COMMENTARY COMMENTARY
BDNF signaling: Harnessing stress to battle mood disorder Pawel Licznerskia and Elizabeth A. Jonasa,1
The link between the onset of major depressive disor- double knockout (DKO) of Gαi1 and Gαi3 results der (MDD) and loss of neurotrophins in the brain is in inhibition of BDNF-induced activation of Akt– of interest to clinicians and basic scientists. MDD is mTORC1 and ERK pathways. shRNA-mediated down- caused by a combination of genetic, environmental, and regulation of Gαi1 and Gαi3 also affects dendritic psychological factors. Trauma, chronic health problems, outgrowth and formation of dendritic spines in the and substance abuse are risks (1), as are grief and other hippocampus. Specific behavioral studies performed purely emotional/cognitive stresses (2, 3). MDD alters by the Marshall team reveal that shRNA knockdown of the expression of neurotrophins, such as brain-derived Gαi1 and Gαi3 or complete DKO cause depression- neurotrophic factor (BDNF). BDNF is required for neu- like behaviors. Their studies suggest that downstream ronal development, survival, and plasticity (4, 5). Brain BDNF signaling via Gαi1 and Gαi3 is necessary not imaging has shown volumetric changes in limbic regions only for sustaining the well-being of neurons but also in depression attributed either to reduced numbers of for normal antidepressive behaviors (11). So, how glia and pyramidal neurons or to their reduced cell body does neurotrophin signaling inside the cell specifically size, accompanied by atrophy of pyramidal neuron api- contribute to the regulation of mental functioning? cal dendrites and decreases in neurogenesis in dentate Neurotrophins, a unique family of polypeptide gyrus (6). These structural alterations most likely contrib- growth factors that include BDNF, regulate prolifera- ute to features of depression, including cognitive tion, proper differentiation, survival, and death of impairment, helplessness, and anhedonia. Neuronal neuronal and nonneuronal cells. Neurotrophins act dysfunction also affects activation of the hypotha- through downstream signaling cascades following lamic–pituitary–adrenal axis (7). Studies show that struc- receptor activation. Brain neurotrophins regulate early tural and functional neuronal alterations in MDD are prenatal brain development and adult central nervous partially rescued by antidepressant treatment. Antide- system plasticity (4). BDNF is the predominant neuro- pressants, in addition to their effects on neurotransmit- trophin in the brain (12). Synthesized as a precursor ter levels, also increase BDNF and enhance expression proBDNF, it is cleaved to release the mature, active of the receptor for BDNF, tropomyosin-related kinase B form (11). Mature BDNF binds preferentially to the (TrkB), in the hippocampus (8). However, the intracellular TrkB receptor, activating downstream signaling path- mechanisms governing the relationship between BDNF, ways such as mitogen-activated protein kinase (MAPK), structural changes in limbic system cells, and clinical phospholipase Cγ, and phosphatidylinositol-3 kinase manifestations of MDD are still unclear. pathway. These signaling cascades regulate transcrip- In PNAS, Marshall et al. (9) demonstrate that tion and dendritic translation of proteins required for Gαi1 and Gαi3, members of the GαI subclass of het- neuronal survival, differentiation, and learning and mem- erotrimeric G proteins, are essential for BDNF/TrkB ory formation in the hippocampus (13, 14). signaling in hippocampus and are down-regulated by Upon elimination of Gαi1 and Gαi3, Marshall et al. chronic stress. G proteins form membrane-associated also observed decreased dendritic branching and re- heterotrimers consisting of α, β, and γ subunits (10). duced numbers of synaptic spines. Substantial loss of There are four main subclasses: Gs, Gi/o, Gq, and CA1 pyramidal neurons was observed in the Gαi1/ G12/13. GαI belongs to the Gi/o subclass and inhibits Gαi3 DKO mouse, which was not found when Gαi1 adenylyl cyclase. Marshall et al. report that reductions and Gαi3 were depleted in adolescent brain using in Gαi1 and Gαi3 levels affect BDNF-induced TrkB shRNA, although this latter model produced alter- endocytosis and activation of signaling pathways down- ations in synaptic structure and the same behavioral stream of TrkB, resulting in depressive behaviors. deficits as the DKO. It is not clear whether loss of In mouse embryonic fibroblasts, they show that the neurons in the DKO mouse hippocampus was caused
aDepartment of Internal Medicine, Yale University, New Haven, CT 06520 Author contributions: P.L. and E.A.J. wrote the paper. The authors declare no conflict of interest. Published under the PNAS license. See companion article on page E3549. 1To whom correspondence should be addressed. Email: [email protected]. Published online March 28, 2018.
3742–3744 | PNAS | April 10, 2018 | vol. 115 | no. 15 www.pnas.org/cgi/doi/10.1073/pnas.1803645115 Downloaded by guest on October 5, 2021 proBDNF
Presynap c
BDNF pro-pep de BDNF
Stress TrkB p75NTR
P P Postsynap c P-eEF2 MEK 1/2 PI3K Apoptosis ATP Growth cone Bcl-2 LTD retrac on ERK 1/2 AKT
mTOR
Neuronal differen a on, survival and synap c plas city
Fig. 1. BDNF binding to TrkB receptor activates signaling cascades responsible for neuronal survival and synaptic plasticity. ProBDNF binds p75NTR and triggers long-term depression and apoptosis. Upon stress, including high-frequency synaptic stimulation, Bcl-2 is recruited to mitochondria to decrease the production of reactive oxygen species (ROS) and enhance effective ATP production; this supports relevant gene transcription and protein translation. Mild acute stress or high frequency synaptic activity recruit and may require BDNF signaling during learning and memory formation and for antidepressant coping strategies.
by loss of developmental targeting of neurons or by enhanced cell and facilitates hippocampal long-term depression, negatively affect- death during neurogenesis or synaptogenesis. Whether longer ing learning and memory formation (Fig. 1) (4, 23). Perhaps the struc- overexpression of Gαi1/Gαi3 shRNA and/or a more challenging tural changes in the Gαi1- and Gαi3-depleted and the DKO mice, stress paradigm might also induce neuronal death remains to be including loss of pyramidal neurons in the hippocampus, might be answered, but it nevertheless seems clear that negative synaptic partially attributed to the actions of proBDNF; the observed synaptic changes are sufficient to produce the depressive features. deficiencies even in the absence of cell death might be related to Chronic stress substantially lowers BDNF (15). The insult cho- apoptotic signaling in the synapses alone (24, 25). sen by Marshall et al. to cause depression in the animals, chronic Stress also regulates intracellular signaling apart from its mild stress, consists of 3 wk of sequential forced swim, restraint, specific effects on BDNF (Fig. 1). Interestingly, brief stress- water and food deprivation, housing in wet sawdust, light/dark induced release of glucocorticoids, at low doses, supports neuro- cycle reversal, and housing in constant illumination or darkness nal branching and survival and positively influences performance (16, 17). In normal rodents, BDNF mRNA levels increase during in spatial learning and memory tasks (26, 27), implicating benefi- early postnatal days in cortex, hippocampus, and cerebellum, cor- cial changes in limbic system networks. Under these conditions, relating with the peak of postnatal synaptogenesis (18). BDNF is corticosterone improves mitochondrial membrane potential and also required in adulthood for proper brain functioning, support- oxidation. The glucocorticoid receptor binds to the antiapoptotic ing neuronal network strengthening and plasticity. Although most B-cell lymphoma 2 protein (Bcl-2). This complex translocates into BDNF homozygous knockout mice die in the first 2 postnatal days, mitochondria to reduce the production of damaging reactive ox- some survive for 2–4 wk (19). These surviving mice nevertheless ygen species (ROS) and prevent the opening of the prodeath show severe impairments in growth and in movement coordina- permeability transition pore (28) while enhancing the supply of tion, and have reduced numbers of cranial and spinal sensory ATP required for proper brain function. The regulation of mito- neurons, albeit with no gross structural abnormalities of the hip- chondrial ATP production by low-dose corticosteroids may pocampus (19, 20). They do, however, show impaired hippo- thereby shape the proper response of neurons to external stress. campal long-term potentiation (LTP) and reduced numbers of In contrast, high levels or chronic stress produce the opposite presynaptic vesicles docked at presynaptic active zones (21), suggest- effects on mitochondria, depolarizing them and predisposing to ing dysfunctional synapses. Apart from BDNF binding to the TrkB activation of apoptotic mechanisms (28). receptor, the precleaved form of BDNF, proBDNF, can act as a sig- Neuronal excitability and synaptic plasticity require high naling molecule in the opposite manner to mature BDNF. ProBDNF mitochondrial fidelity (29, 30). Energy-dependent activities include binds specifically to the p75 neurotrophin receptor (p75NTR), a mem- calcium clearance in a timely manner, rapid actin cytoskeletal rear- ber of the tumor necrosis factor superfamily (22). Activation of p75NTR rangements, trafficking of synaptic vesicles, resetting of ion gradi- decreases the complexity of neuronal projections, triggers apoptosis, ents after action potential firing, and new protein phosphorylation
Licznerski and Jonas PNAS | April 10, 2018 | vol. 115 | no. 15 | 3743 Downloaded by guest on October 5, 2021 in response to synaptic stimulation (31). These events, crucial for by exquisitely timed eEF2 dephosphorylation and increased neuroplasticity, are regulated by the timing and availability of mi- translation of specific synaptic proteins. In summary (Fig. 1), the tochondrial energy supply. In cultured hippocampal neurons, high-frequency stimulation that produces LTP is a stress to neu- BDNF treatment causes accumulation of mitochondria at presyn- rons and mitochondria that is alleviated by intracellular events that aptic sites (32) where mitochondria contribute to synaptic vesicle produce synaptic strengthening. Analogously, gene transcription docking and reserve pool galvanization (33–35). Specific phos- and translation of specific proteins in response to synaptic activity phorylation events may relate to mitochondrial ATP production in the limbic system may be necessary for the proper response to during hippocampal synaptic plasticity downstream of NMDA re- stress to prevent depression and enhance positive cognitive cop- ceptor stimulation. For example, phosphorylation of eukaryotic ing strategies. Loss of activation of growth factor-supported sig- elongation factor 2 (eEF2) within the first few minutes after stim- naling pathways contributes to faulty responses to neuronal ulation results in decreased overall protein synthesis (36), followed activity and stress.
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