Brain-derived neurotrophic factor mediates the activity-dependent regulation of inhibition in neocortical cultures - PubMed (original) (raw)
Brain-derived neurotrophic factor mediates the activity-dependent regulation of inhibition in neocortical cultures
L C Rutherford et al. J Neurosci. 1997.
Abstract
The excitability of cortical circuits is modulated by interneurons that release the inhibitory neurotransmitter GABA. In primate and rodent visual cortex, activity deprivation leads to a decrease in the expression of GABA. This suggests that activity is able to adjust the strength of cortical inhibition, but this has not been demonstrated directly. In addition, the nature of the signal linking activity to GABA expression has not been determined. Activity is known to regulate the expression of the neurotrophin brain-derived neurotrophic factor (BDNF), and BDNF has been shown to influence the phenotype of GABAergic interneurons. We use a culture system from postnatal rat visual cortex to test the hypothesis that activity is regulating the strength of cortical inhibition through the regulation of BDNF. Cultures were double-labeled against GABA and the neuronal marker MAP2, and the percentage of neurons that were GABA-positive was determined. Blocking spontaneous activity in these cultures reversibly decreased the number of GABA-positive neurons without affecting neuronal survival. Voltage-clamp analysis of inhibitory currents demonstrated that activity blockade also decreased GABA-mediated inhibition onto pyramidal neurons and raised pyramidal neuron firing rates. All of these effects were prevented by incubation with BDNF during activity blockade, but not by neurotrophin 3 or nerve growth factor. Additionally, blockade of neurotrophin signaling mimicked the effects of activity blockade on GABA expression. These data suggest that activity regulates cortical inhibition through a BDNF-dependent mechanism and that this neurotrophin plays an important role in the control of cortical excitability.
Figures
Fig. 2.
GABA immunoreactivity in cortical cultures.A, MAP2-positive neurons from cortical cultures after 7 d in vitro, viewed with fluorescein filters.B, Same field of view as in A, using rhodamine filters to show GABA-positive neurons. C, GABA-positive multipolar neuron. D, GABA-positive bipolar neuron. Scale bars: A, B, 10 μm; C, D, 25 μm.
Fig. 1.
Spontaneous activity of cortical neurons in culture. A, Control, A whole-cell recording from a cortical pyramidal neuron after 5 d in vitro. Depolarizing synaptic potentials (arrow) could be detected, which periodically brought the neuron over threshold to fire overshooting action potentials. B, This activity was completely abolished by addition of 0.1 μ
m
TTX to the perfusate.
Fig. 3.
The effects of activity blockade and neurotrophins on the percentage of GABA-positive neurons in cortical cultures.A, Cultures were treated with 0.1 μ
m
TTX, either alone (TTX) or in the presence of 25 ng/ml BDNF (TTX + BDNF), 50 ng/ml NGF (TTX + NGF), or 25 ng/ml NT3 (TTX + NT3) for 2 d; *significantly different from control, p< 0.01. B, The effects of different doses of BDNF on the ability of TTX to reduce the percentage of GABA-positive neurons were determined. TTX (0.1 μ
m
) was applied in the presence of the indicated concentration of BDNF for 2 d and the percentage of GABA-positive neurons determined. For each condition in_A_ and B, the ratio of GABA-positive to GABA-negative neurons was determined, and these values are expressed as a percent of the values obtained for control cultures (control = 100%, dashed line).
Fig. 4.
The effects of Trk receptor blockade on the percentage of GABA-positive neurons. K252a, a blocker of Trk receptor signaling, was applied for 2 d at the indicated concentration (10, 50, or 200 n
m
) and the percentage of GABA-positive neurons determined. The effect of BDNF (25 ng/ml) and TTX (0.1 μ
m
) in the presence of K252a (200 n
m
) for 2 d was also determined (TTX+BDNF+K252a). Numbers are expressed as a percentage of the value obtained for control cultures (control = 100%,dashed line); *significantly different from control,p < 0.05; **significantly different from control,p < 0.001.
Fig. 5.
The activity-dependent reduction in the percentage of GABA-positive neurons is reversible. Cultures were treated with TTX (0.1 μ
m
) for 2 d. Cultures were then fixed, processed, and counted immediately (TTX); washed for 2 d before fixation (TTX/WASH); or washed and BDNF (25 ng/ml) added for 2 d before fixation. Numbers are expressed as a percentage of the value obtained for control cultures (control = 100%, dashed line); *significantly different from control, p < 0.05; **significantly different from control, p < 0.01.
Fig. 6.
Activity blockade reduces inhibition onto pyramidal neurons. A, Representative voltage-clamp recordings of spontaneous IPSCs from pyramidal neurons grown in control medium (CONTROL) in medium supplemented with 0.1 μ
m
TTX for 2 d (TTX) or in medium supplemented with TTX and BDNF (25 ng/ml) for 2 d.B, Frequency of spontaneous IPSCs from pyramidal neurons grown under the conditions indicated in A(n = 8 neurons in each condition).C, Total inhibitory current integrated over time, from the same population as in B; *significantly different from control (Student’s t test, p< 0.04); **p < 0.01.
Fig. 7.
Activity blockade increases pyramidal neuron firing rates. A, Representative current-clamp recordings of spontaneous firing from pyramidal neurons grown in control medium (CONTROL), in medium supplemented with 0.1 μ
m
TTX for 2 d (TTX), or in medium supplemented with TTX and BDNF (25 ng/ml) for 2 d (TTX + BDNF). B, Average spike frequency of pyramidal neurons grown for 2 d under the conditions described in_A_ or in TTX + 50 ng/ml NGF (TTX + NGF) or TTX + 25 ng/ml NT3 (TTX + NT3); *significantly different from TTX (Student’s t test,p < 0.01).
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