Modulation of inhibitory synaptic transmission by brain-derived neurotrophic factor

The development and function of the nervous system are strictly regulated by molecular signals and synaptic activity. Members of the neurotrophin family of proteins have been found to play varied roles in developing and mature nervous systems. The neurotrophin brain-derived neurotrophic factor (BDNF) potentiates excitatory synapses in a variety of systems by promoting presynaptic transmitter release. The existing evidence indicates that BDNF attenuates inhibitory transmission, but reports differ considerably in their characterization of the effect and proposed mechanisms. I examined the effects of exogenously applied BDNF on excitatory and inhibitory postsynaptic currents (EPSCs and EPSCs) recorded from functionally identified glutamatergic neurons in dissociated rat hippocampal cultures, and found that BDNF exerted differential effects at the two synapse types—increasing amplitude of EPSCs, but slightly decreasing that of EPSCs. Furthermore, when recording from GABAergic neurons, I found that BDNF increased the IPSC amplitude. Investigation of BDNF-induced changes in miniature EPSCs and EPSCs indicated that these differential BDNF effects reflect distinct pre- and postsynaptic mechanisms. An increased mini frequency was found at all synapses, indicating elevated presynaptic transmitter secretion; a change in the amplitude of mini EPSCs was found only when recording from GABAergic cells, suggesting a selective postsynaptic modulation of GABA responses.; Selective postsynaptic mechanisms were further examined by comparing BDNF's effect on GABA-induced currents recorded from glutamatergic vs. GABAergic cells. For GABAergic but not glutamatergic postsynaptic cells, BDNF induced a shift in the reversal potential (E_IPSC) towards more positive levels, hence reducing the inhibitory action of IPSCs. This BDNF-induced shift in E_IPSC was blocked by furosemide, an inhibitor of K+/Cl − cotransporters. Because furosemide blocks several different K+/Cl− cotransporters, further experiments were necessary to investigate the specific cotransporter involved in the BDNF effect on GABAergic synapses. Electrophysiological recordings confirmed the existence of KCC2 K+/Cl− cotransporter activity and immunostaining experiments showed expression of KCC2 in these cultures. In addition, I showed that the BDNF-induced effect on E_IPSC correlates with the existing level of KCC2 activity in the postsynaptic cell. Thus BDNF may decrease the efficacy of inhibitory synapses by acute postsynaptic down-regulation of Cl− transport, in addition to its well-known presynaptic effect.