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BDNF Helps Release Cannabinoids in the Hippocampus

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Article

BDNF Helps Release Cannabinoids in the Hippocampus

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Brain derived neurotrophic factor (BDNF) belongs to the neurotrophin gene family and has well established roles in neuronal survival, development and maturation as well as synaptic transmission and plasticity. Impairment of BDNF has been associated with deficits of learning tasks and memory in mouse models. Disruption of BDNF signaling has been associated with several neurological disorders including anxiety, depression and schizophrenia. It has been shown that there is a decrease in the levels of BDNF in post-mortem tissues of patients suffering from depression and schizophrenia.  Conditional mutants of mice lacking BDNF show decreased anxiety in behavioral tests.  Therefore BDNF is considered as a major therapeutic target for neurological disorders.

Neurotransmission is a process by which neurons communicate with each other. Neurotransmitters are molecules that are released in the process of neurotransmission. The neurotransmitters can either be excitatory (eg. Glutamate) or inhibitory (eg. GABA). In the hippocampus and cortex, BDNF can modulate inhibitory (GABAergic) neurotransmission. The acute effect of BDNF tends to be suppressive – a decrease in GABA release. However, the underlying mechanisms explaining how BDNF causes the decrease in GABA release in the hippocampus is unclear.  This is partly because the effects of BDNF are dependent on age, sex, cell type and developmental stage of the brain.  Another reason why research has yet to answer this question is the presence of tropomyosin receptor kinase B (TrkB) receptors on both pre- and post- synaptic sites, which BDNF binds to. BDNF can bind to presynaptic TrkB receptors and exert its effect on postsynaptic TrkB receptors or vice-versa, presenting two possible paths of effect. This is why studying the effects of BDNF on GABAergic neurotransmission is challenging. 


In order to understand the mechanism of BDNF on inhibitory neurotransmission, we first isolated inhibitory currents via application of glutamate receptor antagonists. Whole cell patch clamp recordings were conducted to understand the effects of BDNF on spontaneous inhibitory activity. Patch clamp is a technique used to study currents in individual neurons. 


We found that the BDNF binds to postsynaptic TrkB receptors and its effect is expressed presynaptically. Furthermore, we noted that the BDNF/TrkB interactions causes the release of an cannabinoid, 2-AG. 2-AG is a retrograde messenger. Retrograde messengers are released from postsynaptic sites to act on presynaptic cannabinoid receptors. 2-AG acts on the presynaptic cannabinoid type 1 receptor (CB1R) which causes a suppression of GABA release. In short, BDNF acts via postsynaptic TrkB receptors by causing the release of endogenous cannabinoids that act retrogradely to suppress GABA release. This is a novel mechanism of BDNF that has been identified in the hippocampus. Our study adds to the growing evidence of interactions between BDNF and the endocannabinoid (eCB) signaling system. It also raises the question of whether BDNF can interact with other neuromodulatory systems to exert the inhibitory effects on neurotransmission in different brain areas. Understanding the mechanism for each of these interactions will help in understanding the physiological role of BDNF and eCBs in the context of synaptic transmission regulation. 


Future research will focus on understanding how endogenous BDNF can affect synaptic transmission and/or plasticity.  The results can be extended to other regions of the brain including the motor cortex, prefrontal cortex and mid-brain. Rather than positioning BDNF as a therapeutic target, we can target the downstream signaling partners of BDNF. For instance, in the current work, we have shown that BDNF can interact with endocannabinoids to suppress neurotransmission. By targeting the cannabinoid receptor or enzymes or ligands that are downstream of BDNF/TrkB, we can alter the effects of BDNF. Furthermore, BDNF has region-specific effects in the brain which makes this approach suitable for treatment at precise locations of the brain. Understanding the mechanisms and signaling pathways of BDNF for each region will help us uncover several novel targets for treating neurological disorders. 


Read the article here: Selvam, R., Yeh, M. L., & Levine, E. S. (n.d.). Endogenous cannabinoids mediate the effect of BDNF at CA1 inhibitory synapses in the hippocampus. Synapse, 0(0), e22075. https://doi.org/10.1002/syn.22075

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