Inhibition of GABA_ASynaptic Responses by Brain-Derived Neurotrophic Factor (BDNF) in Rat Hippocampus

Abstract

Brain-derived neurotrophic factor (BDNF) is one of neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. Although the expression of BDNF and its receptor TrkB still occurs in the adult stage, their physiological role in the mature CNS is not fully understood. In the present study we examined in detail the possibility that BDNF modulates synaptic neurotransmissions by using patch-clamp technique in rat hippocampal CA1 region. BDNF (20 -100 ng/ml) did not show any appreciable effect on evoked EPSCs, but it markedly reduced both evoked and spontaneous IPSCs within 5 min, and the reduction persisted while BDNF was present. BDNF also attenuated GABA A receptor-mediated response to applied GABA. However, BDNF failed to attenuate IPSCs when the postsynaptic pyramidal neuron was loaded intracellularly with 200 nM K252a, an alkaloid that inhibits the kinase activity of Trk receptor family, through the patch pipette. Intracellular application of 200 nM K252b, a weaker inhibitor of Trk-type kinase, did not affect the inhibition. The attenuating effect also was prevented by postsynaptic injection of U73122 (5 M), a broad-spectrum PLC inhibitor, and by strong chelation of intracellular Ca 2ϩ with 10 mM BAPTA. These data suggest that BDNF modulates GABA A synaptic responses by postsynaptic activation of Trk-type receptor and subsequent Ca 2ϩ mobilization in the CNS.Key words: BDNF; GABA A receptor; disinhibition; plasticity; LTP; hippocampus Brain-derived neurotrophic factor (BDNF) is one of the neurotrophins involved in the development and maintenance of both the peripheral nervous system and CNS. During brain development neurotrophins and their receptors display distinct stage-and tissue-specific patterns of expression (Ernfors et al., 1990a;Phillips et al., 1990;Merlio et al., 1992). BDNF mRNA is observed in the embryonic stage and is still present in the postnatal and adult stages (Ernfors et al., 1990b;Maisonpierre et al., 1990; Freidman et al., 1991). In the adult stage its expression level is modulated dramatically by neuronal activity (Falkenberg et al., 1992;Patterson et al., 1992;Rocamora et al., 1992;Bengzon et al., 1993;Kokaia et al., 1993). Moreover, expression of TrkB, a functional BDNF receptor, not only increases during embryonic development but also continues to increase until several weeks after birth in the hippocampus (Masana et al., 1993;Ringstedt et al., 1993). These observations suggest that in the adult CNS dynamic change in BDNF level still can trigger neuronal plasticity via activation of TrkB. Indeed, neurotrophins are secreted by neurons in both a constitutive and an activity-dependent manner Thoenen, 1995, 1996;Griesbeck et al., 1995;Thoenen, 1995;Goodmann et al., 1996). Additionally, BDNF induces long-lasting enhancement of synaptic transmission (Kang and Schuman, 1995) and facilitates the induction of long-term potentiation (LTP) in the hippocampus (Figurov et al., 1996); however, the site and mechanism of action of BDNF remain unclear, becau...

BDNF and NT-3 Increase Velocity of Activity Front Propagation in Unidimensional Hippocampal Cultures

“…Thus the measured effects that we report here were long-term and not acute, as previously studied in BDNF (Brunig et al 2001;Frerking et al 1998;Kang and Schuman 1995;Kim et al 1994;Levine et al 1995;Li et al 1998;Tanaka et al 1997) or NT-3 (Kang and Schuman 1995;Kim et al 1994).…”

Activity-dependent scaling of GABAergic synapse strength is regulated by brain-derived neurotrophic factor

“…It is important to note that BDNF has vastly different effects on GABA A receptor trafficking over shorter time courses. Acutely, BDNF instead reduces the strength of GABAergic synapses by suppressing the amplitude of inhibitory synaptic currents (Tanaka et al, 1997;Frerking et al, 1998;Brunig et al, 2001;Cheng and Yeh, 2003). Recent experiments from this laboratory also showed that this suppression is mediated by activation of the TrkB receptor leading to an increase in the internalization of GABA A receptors (C.C.…”

The Role of Brain-Derived Neurotrophic Factor Receptors in the Mature Hippocampus: Modulation of Long-Term Potentiation through a Presynaptic Mechanism involving TrkB

“…In contrast, BDNF has been shown by different groups to enhance not only presynaptic transmitter release but also postsynaptic transmission through NMDA channels in cultured hippocampal neurons (Levine et al, 1995(Levine et al, , 1998. Interneurons are also a potential locus for BDNF action, because BDNF deficiency clearly inhibits the differentiation of these neurons (Jones et al, 1994), and acute application of BDNF has been shown to decrease inhibition in slices from adult animals (Tanaka et al, 1997;Frerking et al, 1998). Thus, it is not certain whether the targets of BDNF relevant for LTP are presynaptic CA3 afferents, postsynaptic CA1 pyramidal cells, interneurons, or all three.…”

“…In addition to pyramidal neurons, the CA1 region also contains scattered GABAergic interneurons, a majority of which express calbindin (Shetty and Turner, 1998). GABAergic interneurons have been shown to express TrkB and to be responsive to BDNF Tanaka et al, 1997;Vicario-Abejón et al, 1998). Because these neurons do not express ␣CaMKII (Sík et al, 1998;Zhang et al, 1999), they are unlikely to be affected by expression of the CaMKcre transgene.…”

“…Considerable debate exists regarding the site at which BDNF acts to modulate synaptic efficacy in the hippocampus. BDNF has been reported to potentiate basal excitatory synaptic transmission via a presynaptic mechanism in cultured hippocampal neurons (Lessmann et al, 1994;Li et al, 1998) and in hippocampal slices (Kang and Schuman, 1995) (but see Figurov et al, 1996;Patterson et al, 1996;Tanaka et al, 1997;Frerking et al, 1998;Gottschalk et al, 1998). Additionally, BDNF increases the ability of the presynaptic terminal to release transmitter repetitively at high frequency (Figurov et al, 1996;Gottschalk et al, 1998).…”