Date of Completion

9-24-2018

Embargo Period

9-24-2019

Keywords

BDNF, endocannabinoid, trkB, CB1, synaptic transmission

Major Advisor

Dr. Eric S. Levine

Associate Advisor

Dr. Richard E. Mains

Associate Advisor

Dr. Xinming Ma

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

Endocannabinoids (eCBs) are important mediators of synaptic plasticity, acting as retrograde messengers because they are released on demand from postsynaptic sites and activate presynaptic type I cannabinoid (CB1) receptors to suppress neurotransmitter release at both excitatory and inhibitory synapses. Similarly, brain derived neurotrophic factor (BDNF) is also a potent neuromodulator of synaptic transmission. The effect of BDNF on synaptic transmission is mediated by tropomyosin receptor kinase B (trkB) receptors. Both CB1 and trkB receptors are highly expressed at synapses throughout the neocortex and hippocampus. There is a growing evidence of cross talk between eCB and BDNF signaling. In particular, studies in our lab have shown that BDNF can trigger the release of endogenous endocannabinoids via phospholipase C signaling at inhibitory synapses in somatosensory cortex. It is not known whether BDNF-induced eCB release also occurs at excitatory synapses and in regions other than the neocortex. In the present studies, we examined a potential crosstalk between BDNF and eCB release at excitatory synapses in neocortex and inhibitory synapses in the hippocampus. Using whole cell patch clamp recordings and pharmacological manipulations in mouse brain slices, we found at layer 5 excitatory synapses of somatosensory cortex, BDNF by Rajamani Selvam – University of Connecticut, 2018 itself had little effect on spontaneous excitatory activity. However, blocking CB1 receptors or disrupting eCB release unmasked a significant BDNF-induced increase in the frequency of spontaneous excitatory synaptic events. These results suggest that BDNF induces the release of endogenous eCBs at these synapses that has a mitigating effect on the direct presynaptic effects of BDNF. We also found evidence for BDNF-induced eCB release at inhibitory synapses in hippocampus. Acute application of BDNF reduced spontaneous inhibitory synaptic activity in CA1 pyramidal neurons and this effect of BDNF was triggered by postsynaptic trkB activation. The suppressive effect of BDNF was mediated by eCB signaling because it was completely prevented by either blocking CB1 receptors or by inhibiting eCB release. Further, we identified 2-AG as the specific eCB released by BDNF because blocking the synthesis of 2-AG prevented the effect of BDNF, whereas blocking 2-AG degradation enhanced the effect of BDNF. Collectively, these results suggest that in the hippocampus, BDNF-trkB signaling induces the release of the endogenous cannabinoid 2-AG, which acts as a retrograde messenger at presynaptic CB1 receptors to suppress GABA release. Taken together, these studies indicate that BDNF induces the release of eCBs at both inhibitory and excitatory synapses in neocortex, and the effects of BDNF at inhibitory synapses extend to the hippocampus. These studies contribute to the understanding of the physiological roles of BDNF and eCB signaling in the context of synaptic plasticity.

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