Brain-derived neurotrophic factor prevents low-frequency inputs from inducing long-term depression in the developing visual cortex - PubMed (original) (raw)

Brain-derived neurotrophic factor prevents low-frequency inputs from inducing long-term depression in the developing visual cortex

S Kinoshita et al. J Neurosci. 1999.

Abstract

Brain-derived neurotrophic factor (BDNF) is reported to enhance synaptic transmission and to play a role in long-term potentiation in hippocampus and neocortex. If so, a shortage or blockade of BDNF might lead to another form of synaptic plasticity, long-term depression (LTD). To test this possibility and to elucidate mechanisms if it is the case, EPSCs evoked by test stimulation of layer IV were recorded from layer II/III neurons in visual cortical slices of young rats in the whole-cell voltage-clamp mode. LTD was induced by low-frequency stimulation (LFS) at 1 Hz for 10-15 min if each pulse of the LFS was paired with depolarization of neurons to -30 mV but was not induced if their membrane potentials were kept at -70 mV. Such an LTD was blocked by exogenously applied BDNF, probably through presynaptic mechanisms. Suppression of endogenous BDNF activity by the anti-BDNF antibody or an inhibitor for BDNF receptors made otherwise ineffective stimuli (LFS without postsynaptic depolarization) effective for LTD induction, suggesting that endogenous BDNF may prevent low-frequency inputs from inducing LTD in the developing visual cortex.

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Figures

Fig. 1.

Dependence of LTD induction on postsynaptic membrane potential. A, An example of ineffectiveness for LFS to induce LTD when the membrane potential of a postsynaptic neuron was clamped at −70 mV. At the top are shown examples of EPSCs recorded at the time point indicated by corresponding letters in the bottom graph. Each record is obtained by superimposition of six consecutive sweeps. The peak amplitude and the initial slope of EPSCs are plotted against time in the_top_ and bottom graphs, respectively. The value is expressed as the percentage of the mean of 60 responses before LFS. The time when LFS was applied to layer IV is indicated by a_horizontal bar_. B, An example of LTD induced by LFS that was paired with depolarization of a postsynaptic neuron to −30 mV. The peak amplitude and the initial slope of EPSCs are plotted against time in the top two graphs. In the_bottom two graphs_, the series resistance of the electrode and the membrane resistance of the cell are plotted against time. Other conventions are the same as in A.

Fig. 2.

Time courses of the mean EPSC slope. For each cell, the mean slope of six consecutive EPSCs was calculated as a percentage of that of 30 control EPSCs before LFS. Vertical bars indicate twice the SEM. In A, LFS* indicates that its duration was 10 min for seven cells and 15 min for the other two cells. The values after cessation of the LFS were combined as described in Results. Thus, the_numbers_ in parentheses along the abscissa indicate the time for the latter two cells. In all nine cells the membrane potential was kept at −70 mV throughout recordings. In_B_ and C, LFS was paired with depolarization of recorded cells to −30 and −50 mV, respectively. The duration of LFS was 10 min, as indicated by horizontal bars. Other conventions are the same as in A. In_D_, recorded cells were depolarized to −30 mV without layer IV stimulation, as indicated by the horizontal bar. Other conventions are the same as in_A_.

Fig. 3.

Blockade of LTD by BDNF (A), and effective (B) and ineffective (C) antagonism by K252a applied through the medium and K252b injected into a postsynaptic neuron, respectively. The initial slope of EPSCs is plotted against time in the graphs. The value is expressed as the percentage of the mean of 60 responses before LFS. An open, horizontal bar indicates the period during which BDNF was applied to the slice. In B, K252a (300 n

) was applied to a slice, as indicated by a_shaded, horizontal bar_, simultaneously with BDNF. In_C_, K252b (200 n

) was injected into a neuron through a patch pipette. Other conventions are the same as in Figure1_A_.

Fig. 4.

Time courses of the mean EPSC slope in the conditions as indicated. Conventions are the same as in Figure 2. In_A_, BDNF was applied to slices, as indicated by the_open, horizontal bar_, and then LFS was paired with −30 mV depolarization of recorded neurons during the period indicated by the filled horizontal bar. In B, BDNF and K252a were applied to slices through the perfusion medium, as indicated by horizontal bars. In C, K252b was injected into recorded neurons through patch pipettes, and BDNF was applied to slices through the medium, as indicated by the open, horizontal bar.

Fig. 5.

A fluorescent image of a pyramidal neuron into which a mixture of K252b and rhodamine was injected through a patch pipette, which is seen to be attached to the soma. This cell was located in layer II/III of the cortex so that the right side of the figure corresponds to layer I of the cortex. Scale bar, 20 μm.

Fig. 6.

Specificity of the anti-BDNF antibody.A, Western blot. NGF (purified mouse submandibular β-NGF, 2.6 ng), BDNF (recombinant human BDNF, 2.5 ng), and NT-3 (recombinant human NT-3, 2.5 ng) were loaded in respective lanes. The blot was stained with the anti-BDNF antibody. An arrow indicates a band corresponding to a subunit of BDNF with molecular mass of 14 kDa.B, Assay of activity of the anti-BDNF antibody. Action of the antibody on ChAT activity enhanced by BDNF or NGF was examined in the conditions as indicated at the bottom. Each_column with short bars_ indicates the mean ± SD of the mean for the four determinations.

Fig. 7.

Emergence of LTD during the inhibition of activity of endogenous BDNF. A, An example of LTD induced by LFS without postsynaptic depolarization in a slice that was perfused with the anti-BDNF antibody at the concentration of 1 μg/ml. Other conventions are the same as in Figure 1_A_. In the_bottom graph_, the membrane resistance of this neuron is plotted against time. B, Time course of the mean EPSC slope for 10 neurons. Slices containing these neurons had been incubated with the anti-BDNF antibody. Other conventions are the same as in Figure 2.

Fig. 8.

Schematic diagrams showing the two models for the blocking action of BDNF on LTD. In A, BDNF is hypothesized to be derived from presynaptic sites and to serve as an inhibitor for an LTD expression factor that would be released from postsynaptic sites. In this model, LFS is supposed to induce a mild level of depolarization and a consequent rise of Ca2+ in postsynaptic sites through activation of glutamate receptors (Glu-R) and voltage-dependent Ca2+ channels (VDCC). This rise of Ca2+ would activate an unknown process, which in turn would release or produce the LTD expression factor. This factor would decrease transmitter release from presynaptic terminals for a long time. The activation of TrkB by BDNF would then suppress the action of this factor in presynaptic terminals. In B, BDNF itself is hypothesized to operate as an LTD-blocking or a synaptic transmission-maintaining factor. The LFS-induced rise in postsynaptic Ca2+ would activate an unknown factor, possibly protein phosphatases, which would suppress the release or production of BDNF at postsynaptic sites. This would in turn lead to a shortage of BDNF at presynaptic terminals. Thus, LFS without support of BDNF would lead to a decrease in transmitter release from presynaptic terminals for a long time.

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Brain-derived neurotrophic factor prevents low-frequency inputs from inducing long-term depression in the developing visual cortex - PubMed (original) (raw)