Study of mechanisms underlying the effects of brain-derived neurotrophic factor (BDNF) on the developmental acquisition of graviceptive behaviour

Abstract

Refinement and consolidation of synaptic inputs at single cell level is known to orchestrate the establishment of neural circuitry during brain development. Plasticity of these networks is governed by both pre- and postsynaptic mechanisms. Maturation of inhibitory GABAergic circuitry in the cortex is known to be regulated by brain-derived neurotrophic factor (BDNF) and its receptor tropomyosin-related kinase B (TrkB). We demonstrated that chronic release of BDNF from an Elvax slice implanted onto the brainstem vestibular nucleus (VN) of neonatal rats advanced the emergence of negative geotaxis, a behavioral indicator of gravity-detection, for 2 days. To delineate the role of BDNF on γ-aminobutyric acid (GABA) transmission within the VN, the postnatal profile of GABA transmission among medial vestibular (MV) neurons was studied using whole-cell patch-clamp technique. Theta-burst stimulation, a stimulus protocol that induces synaptic plasticity, triggered long-term depression of GABAA receptor-mediated evoked postsynaptic currents (LTDGABA) in postnatal day (P) 4 neurons. The same stimulus, however, induced long-term potentiation of such current (LTPGABA) in P14 neurons. Given that GABAA receptor-mediated postsynaptic action in many neural regions changes from excitatory to inhibitory during postnatal development, it becomes crucial to determine whether such a switch occurs in postnatal VN. Gramicidin-perforated whole-cell patch-clamp data showed that GABAA receptor-mediated current in neonatal VN was excitatory in nature and that the reversal potential of GABAA receptor (EGABA) became more negative from P4 to P14. We further demonstrated that GABAA receptor-mediated postsynaptic action in VN switched from depolarization to hyperpolarization between P9 and P12. When treated with BDNF, P4 and P7 MV neurons exhibited a decrease in the magnitude of LTDGABA resulting in GABAergic current that was bigger than that of the control evoked by the same stimulus. This suggests that BDNF enhances the activity of GABAergic input in early postnatal VN. At P14, after the effect of GABA switched from depolarizing to hyperpolarizing, incubation of the brainstem slice with BDNF attenuated GABAA receptor-mediated inhibitory current in MV neurons. This resulted in the induction of LTDGABA, a form of plasticity that was usually observed only in the early postnatal stage. With blockade of endocannabinoid (eCB) receptor CB1R that mediates retrograde signaling and presynaptic release of GABA, BDNF changed the efficacy of GABAergic synapses in P4 and P7 VN from LTDGABA to LTPGABA. This indicates that eCB receptor in the VN modulates BDNF-induced change in efficacy of GABAergic transmission. In addition, TrkB receptor agonist 7,8-dihydroxyflavone (7,8-DHF) mimicked the effect of BDNF on GABAergic synaptic plasticity of MV neurons during early postnatal development. Neonatal rats pre-implanted with 7,8-DHF-loaded Elvax slice showed pattern of GABAergic plasticity that was only seen later in postnatal life. Our results therefore demonstrate that BDNF and the activation of TrkB receptor advanced postnatal emergence of graviceptive behavior by enhancing excitatory GABAergic transmission in MV neurons of P4 and P7 rats. This action was modulated by eCB-mediated presynaptic plasticity. Furthermore, BDNF attenuated inhibitory GABAergic transmission of MV synapses in P14 rats. Taken together, BDNF modifies plasticity of the developing vestibular network and behavioral expression of vestibular function.