Brain-Derived Neurotrophic Factor Mediates the Activity-Dependent Regulation of Inhibition in Neocortical Cultures

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.

Added astroglia promote greater synapse density and higher activity in neuronal networks

“…In adult stomatogastric ganglion neurons in culture, a change from tonic to bursting action potentials is accompanied by changes in the ratio of inward:outward currents (Turrigiano et al, 1995). Deprivation of visual cortical activity downregulates GABAergic input through reduced BDNF (Rutherford et al, 1997); but BDNF-independent mechanisms also control quantal current amplitudes through postsynaptic polarization (Leslie et al, 2001). Even the ratio of two inward currents, AMPA and NMDA, are scaled together with activity changes to keep a constant receptor ratio (Watt et al, 2000).…”

“…Turigiano's group has found ranges for balancing of inward and outward currents that prevent bursting during changes in input excitation (Turigiano et al, 1995). They also have evidence for control of this synaptic scaling by brain-derived growth factor (BDNF) (Rutherford et al, 1997), postsynaptic polarization (Leslie et al, 2001) and Calcium/Calmodula-dependent protein Kinase II (CaMKII) (Pratt et al, 2003). Here, we probe excitatory synapses with glutamate and inhibitory GABA A receptors with bicuculline (Barbin et al, 1993), and determine receptor densities to further characterize the effect of medium conditioned by either astroglia or glia on network dynamics.…”

Mechanisms of action of antidepressants: from neurotransmitter systems to signaling pathways

“…The mechanisms involved in this phenomenon are not known, although it could be due to a stress-mediated decrease in brain derived neurotropic factor (BNDF), a molecule involved in neurogenesis [50]. Another possibility involves a reduction in functional genes such as bcl-2, or decreased neurogenesis of GABA neurons if they undergo substantial turnover [51].…”

Neurotrophin signaling among neurons and glia during formation of tripartite synapses

“…Prolonged signaling by neurotrophins promotes quantal scaling of excitatory and inhibitory synapses in postnatal neural networks by modulating postsynaptic receptors (Rutherford et al, 1997;Rutherford et al, 1998). At glutamatergic synapses, BDNF promotes maturation of silent synapses by increasing the translocation of the GluR2 AMPA-receptor subunit to the neuronal surface in neocortical neurons (Narisawa-Saito et al, 1999;Narisawa-Saito et al, 2002).…”