BDNF Regulates the Intrinsic Excitability of Cortical Neurons

Many developing neurons experience dramatic changes in the number or strength of the synaptic connections they receive (Shatz 1990; Constantine-Paton and Cline 1998). At the same time they must prevent firing rates from falling too low or saturating, both to remain responsive to their inputs and to allow activity to selectively strengthen or weaken individual synaptic connections (Bear and Malenka 1994). This problem can be solved if the excitability of each neuron in a network can be independently adjusted to keep firing rates within functional boundaries (Turrigiano 1999). Recent work has identified two distinct homeostatic mechanisms that may stabilize neuronal activity in the face of large changes in synaptic drive. First, ongoing activity can adjust the intrinsic excitability of cortical neurons by modifying the balance of voltage-dependent conductances (Desai et al. 1999a,b). Second, neurons can scale the strength of excitatory synaptic inputs up or down in response to changes in activity (Lissin et al. 1998; O’Brien et al. 1998; Turrigiano et al. 1998). By stabilizing neuronal firing rates, these two forms of homeostatic plasticity should help neurons remain responsive to their inputs during periods of change in intrinsic neuronal properties or in the number and strength of synaptic inputs (Turrigiano 1999). Activity-dependent synaptic scaling and activity-dependent changes in intrinsic ionic conductances both increase the excitability of pyramidal neurons in response to activity blockade (Turrigiano et al. 1998; Desai et al. 1999a,b). The former does this by globally increasing the amplitude of excitatory postsynaptic currents in a multiplicative manner (Turrigiano et al. 1998). The latter does it by selectively regulating the density of individual ionic currents to increase the firing rate and lower the spike threshold of activity-deprived neurons; sodium currents increase in size, persistent potassium currents decrease, and calcium and transient potassium currents remain the same (Desai et al. 1999a,b). Both forms of plasticity will tend to keep firing rates homeostatically within bounds, suggesting that they act synergistically. This raises the important question of whether they are regulated by the same or by different signaling pathways. Synaptic scaling is mediated in part by the activity-dependent release of the neurotrophin brain-derived neurotrophic factor (BDNF) (Rutherford et al. 1998). BDNF is produced by cortical pyramidal neurons, and the high affinity BDNF receptor TrkB is present on both pyramidal neurons and interneurons (Kokaia et al. 1993; Miranda et al. 1993; Cabelli et al. 1996; Cellarino et al. 1996). BDNF expression, and probably release, is tightly regulated by activity (Isackson et al. 1991; Zafra et al. 1991; Castren et al. 1992; Ghosh et al. 1994; Wetmore et al. 1994; Blochl and Thoenen 1995). Long-term manipulations of BDNF in visual cortex disrupt ocular dominance column segregation (Cabelli et al. 1995, 1997) and experience-dependent modifications of ocular dominance among cortical neurons (Galuske et al. 1996). In addition, long-term manipulation of BDNF in vitro influences cortical dendritic growth (McAllister et al. 1995, 1996, 1997) and the amount of inhibition received by cortical pyramidal neurons (Rutherford et al. 1997), suggesting that BDNF plays an important role in the development of cortical connectivity. We have shown previously that incubating in exogenous BDNF prevents, whereas scavenging endogenous TrkB ligands mimics, the increase in pyramidal neuron excitatory synaptic strengths produced by activity blockade (Rutherford et al. 1998). These data demonstrate that activity blockade scales excitatory synaptic strengths up by reducing the release of endogenous TrkB ligands. In addition to a role in the long-term regulation of synaptic strengths, BDNF has been shown to influence the expression of voltage-dependent conductances in both cell lines and neurons (Gonzalez and Collins 1997; Lesser et al. 1997; Oyelese et al. 1997; Sherwood et al. 1997). Because activity blockade increases the intrinsic excitability of cortical neurons by selectively regulating the balance of voltage-dependent conductances (Desai et al. 1999a), this suggested that BDNF might also be the signal linking changes in activity to changes in intrinsic neuronal excitability. Here we explore the possibility that activity regulates the intrinsic excitability of cortical neurons through changes in the release of BDNF. We find that the leftward and upward shift in pyramidal neuron FI curves produced by activity blockade can be prevented by coapplication of BDNF and that a TrkB–IgG fusion protein mimics the effects of activity blockade. These data suggest that the same activity-dependent signal, BDNF, produces a coordinated change in both the amplitude of excitatory synaptic inputs and the function relating that amplitude to the firing rate of the postsynaptic neuron.