| Brain-derived neurotrophic factor (BDNF) has an important regulatory effect in the migration, differentiation, maturation, synapse formation, and synaptic transmission of the GABAergic system. However, the mechanisms by which BDNF is able to mediate all these processes are not clear. To broaden our understanding of the mechanisms by which BDNF regulates GABAergic neurotransmission, the contribution of the PI3 Kinase-Akt, PLC-gamma-Ca2+, and MAP kinase pathways to BDNF-induced enhancement of GABAergic neurotransmission was evaluated. Here, we have demonstrated that PI3 Kinase-Akt and MAP kinase pathways contribute to BDNF-induced enhancement of GABAergic current amplitude. Additionally, the MAP kinase pathway also contributes to BDNF-induced enhancement of GABAergic current frequency. In contrast, we found that PLC-gamma pathway does not contribute to BDNF-induced enhancement of GABergic neurotransmission.;To gain a deeper insight into the mechanism by which BDNF induces enhancement of GABAergic neurotransmission, we evaluated the contribution of the BDNF substrate Ankyrin repeat-rich membrane-spanning protein (ARMS) to the regulation of GABAergic neurotransmission. Using hippocampal cultures and specifically manipulating the expression of ARMS proteins levels in pyramid-shaped neurons, we have shown that ARMS regulates basal GABAergic neurotransmission through a presynaptic mechanism. Additionally, we have showed that lowering the ARMS expression blocks the BDNF-induced enhancement of GABAergic neurotransmission and impair the long lasting activation of the MAPK pathway by BDNF in hippocampal neurons. Finally, using ARMS+/- mice, we have demonstrated that decreasing ARMS protein expression levels in vivo impairs inhibitory neurotransmission into CA1 hippocampal pyramidal neurons and decreases the expression of GAD65 and BDNF. Altogether, our results provide evidence that the MAPK pathway and ARMS scaffold protein play a critical role in the regulation of inhibitory neurotransmission by BDNF in hippocampal neurons. |
