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Synaptic depression enables neuronal gain control.

Rothman JS, Cathala L, Steuber V, Silver RA - Nature (2009)

Bottom Line: When granule cells were driven with bursts of high-frequency mossy fibre input, as observed in vivo, larger inhibition-mediated gain changes were observed, as expected with greater STD.Simulations of synaptic integration in more complex neocortical neurons suggest that STD-based gain modulation can also operate in neurons with large dendritic trees.Our results establish that neurons receiving depressing excitatory inputs can act as powerful multiplicative devices even when integration of postsynaptic conductances is linear.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

ABSTRACT
To act as computational devices, neurons must perform mathematical operations as they transform synaptic and modulatory input into output firing rate. Experiments and theory indicate that neuronal firing typically represents the sum of synaptic inputs, an additive operation, but multiplication of inputs is essential for many computations. Multiplication by a constant produces a change in the slope, or gain, of the input-output relationship, amplifying or scaling down the sensitivity of the neuron to changes in its input. Such gain modulation occurs in vivo, during contrast invariance of orientation tuning, attentional scaling, translation-invariant object recognition, auditory processing and coordinate transformations. Moreover, theoretical studies highlight the necessity of gain modulation in several of these tasks. Although potential cellular mechanisms for gain modulation have been identified, they often rely on membrane noise and require restrictive conditions to work. Because nonlinear components are used to scale signals in electronics, we examined whether synaptic nonlinearities are involved in neuronal gain modulation. We used synaptic stimulation and the dynamic-clamp technique to investigate gain modulation in granule cells in acute slices of rat cerebellum. Here we show that when excitation is mediated by synapses with short-term depression (STD), neuronal gain is controlled by an inhibitory conductance in a noise-independent manner, allowing driving and modulatory inputs to be multiplied together. The nonlinearity introduced by STD transforms inhibition-mediated additive shifts in the input-output relationship into multiplicative gain changes. When granule cells were driven with bursts of high-frequency mossy fibre input, as observed in vivo, larger inhibition-mediated gain changes were observed, as expected with greater STD. Simulations of synaptic integration in more complex neocortical neurons suggest that STD-based gain modulation can also operate in neurons with large dendritic trees. Our results establish that neurons receiving depressing excitatory inputs can act as powerful multiplicative devices even when integration of postsynaptic conductances is linear.

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Gain modulation during broad bandwidth single mossy fibre stimulationa, Mixed AMPAR+NMDAR EPSCs in GCs during single MF, Poisson burst-like stimulation (black ticks) at −75mV. Stimulus artifacts subtracted.b, Voltage responses to burst-like MF stimulation with and without tonic inhibition (±inh; black and gray; Ginh = 500 pS) injected via dynamic clamp. Black horizontal bar indicates firing rate measurement window. Vrest = −74mV.c, Average GC input-output relation ±inh for single MF stimulation (n = 7) with Hill fits (Eq. 5).d, Mean between relationship Gexc and MF stimulation rate (f). Blue line is an exponential fit (Eq. 4).e, Gain (green) and offset (orange) changes due to inhibition (±inh) computed from fits in c.
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Figure 4: Gain modulation during broad bandwidth single mossy fibre stimulationa, Mixed AMPAR+NMDAR EPSCs in GCs during single MF, Poisson burst-like stimulation (black ticks) at −75mV. Stimulus artifacts subtracted.b, Voltage responses to burst-like MF stimulation with and without tonic inhibition (±inh; black and gray; Ginh = 500 pS) injected via dynamic clamp. Black horizontal bar indicates firing rate measurement window. Vrest = −74mV.c, Average GC input-output relation ±inh for single MF stimulation (n = 7) with Hill fits (Eq. 5).d, Mean between relationship Gexc and MF stimulation rate (f). Blue line is an exponential fit (Eq. 4).e, Gain (green) and offset (orange) changes due to inhibition (±inh) computed from fits in c.

Mentions: In vivo recordings show that finger extension20 and facial stimulation19 can produce high frequency bursts of MF firing. To examine whether STD-mediated gain modulation can operate under such conditions, we recorded from GCs while stimulating individual MFs with high frequency bursts to mimic activity in vivo19,20. This induced bursts of mixed AMPAR-NMDAR EPSCs under voltage-clamp, confirming reliable MF activation (Fig. 4a). In current-clamp, this produced GC firing19 from a potential of −75mV (Fig. 4b). Firing rate was measured from the 4th stimuli to allow time for EPSC depression to occur21. A 500 pS tonic inhibitory conductance reduced firing (Fig. 4b) and produced a robust reduction in neuronal gain (Fig. 4c) that was 2-fold larger than for the 4-fibre excitation (Fig. 3d and Fig. 4e). The powerful nonlinearity between Gexc and f (Fig. 4d), combined with a purely additive shift in the FGexc relation, accounted for most of the inhibition-mediated gain change (Supplementary Fig. 5), confirming it was mediated predominantly by STD.


Synaptic depression enables neuronal gain control.

Rothman JS, Cathala L, Steuber V, Silver RA - Nature (2009)

Gain modulation during broad bandwidth single mossy fibre stimulationa, Mixed AMPAR+NMDAR EPSCs in GCs during single MF, Poisson burst-like stimulation (black ticks) at −75mV. Stimulus artifacts subtracted.b, Voltage responses to burst-like MF stimulation with and without tonic inhibition (±inh; black and gray; Ginh = 500 pS) injected via dynamic clamp. Black horizontal bar indicates firing rate measurement window. Vrest = −74mV.c, Average GC input-output relation ±inh for single MF stimulation (n = 7) with Hill fits (Eq. 5).d, Mean between relationship Gexc and MF stimulation rate (f). Blue line is an exponential fit (Eq. 4).e, Gain (green) and offset (orange) changes due to inhibition (±inh) computed from fits in c.
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Figure 4: Gain modulation during broad bandwidth single mossy fibre stimulationa, Mixed AMPAR+NMDAR EPSCs in GCs during single MF, Poisson burst-like stimulation (black ticks) at −75mV. Stimulus artifacts subtracted.b, Voltage responses to burst-like MF stimulation with and without tonic inhibition (±inh; black and gray; Ginh = 500 pS) injected via dynamic clamp. Black horizontal bar indicates firing rate measurement window. Vrest = −74mV.c, Average GC input-output relation ±inh for single MF stimulation (n = 7) with Hill fits (Eq. 5).d, Mean between relationship Gexc and MF stimulation rate (f). Blue line is an exponential fit (Eq. 4).e, Gain (green) and offset (orange) changes due to inhibition (±inh) computed from fits in c.
Mentions: In vivo recordings show that finger extension20 and facial stimulation19 can produce high frequency bursts of MF firing. To examine whether STD-mediated gain modulation can operate under such conditions, we recorded from GCs while stimulating individual MFs with high frequency bursts to mimic activity in vivo19,20. This induced bursts of mixed AMPAR-NMDAR EPSCs under voltage-clamp, confirming reliable MF activation (Fig. 4a). In current-clamp, this produced GC firing19 from a potential of −75mV (Fig. 4b). Firing rate was measured from the 4th stimuli to allow time for EPSC depression to occur21. A 500 pS tonic inhibitory conductance reduced firing (Fig. 4b) and produced a robust reduction in neuronal gain (Fig. 4c) that was 2-fold larger than for the 4-fibre excitation (Fig. 3d and Fig. 4e). The powerful nonlinearity between Gexc and f (Fig. 4d), combined with a purely additive shift in the FGexc relation, accounted for most of the inhibition-mediated gain change (Supplementary Fig. 5), confirming it was mediated predominantly by STD.

Bottom Line: When granule cells were driven with bursts of high-frequency mossy fibre input, as observed in vivo, larger inhibition-mediated gain changes were observed, as expected with greater STD.Simulations of synaptic integration in more complex neocortical neurons suggest that STD-based gain modulation can also operate in neurons with large dendritic trees.Our results establish that neurons receiving depressing excitatory inputs can act as powerful multiplicative devices even when integration of postsynaptic conductances is linear.

View Article: PubMed Central - PubMed

Affiliation: Department of Neuroscience, Physiology and Pharmacology, University College London, Gower Street, London WC1E 6BT, UK.

ABSTRACT
To act as computational devices, neurons must perform mathematical operations as they transform synaptic and modulatory input into output firing rate. Experiments and theory indicate that neuronal firing typically represents the sum of synaptic inputs, an additive operation, but multiplication of inputs is essential for many computations. Multiplication by a constant produces a change in the slope, or gain, of the input-output relationship, amplifying or scaling down the sensitivity of the neuron to changes in its input. Such gain modulation occurs in vivo, during contrast invariance of orientation tuning, attentional scaling, translation-invariant object recognition, auditory processing and coordinate transformations. Moreover, theoretical studies highlight the necessity of gain modulation in several of these tasks. Although potential cellular mechanisms for gain modulation have been identified, they often rely on membrane noise and require restrictive conditions to work. Because nonlinear components are used to scale signals in electronics, we examined whether synaptic nonlinearities are involved in neuronal gain modulation. We used synaptic stimulation and the dynamic-clamp technique to investigate gain modulation in granule cells in acute slices of rat cerebellum. Here we show that when excitation is mediated by synapses with short-term depression (STD), neuronal gain is controlled by an inhibitory conductance in a noise-independent manner, allowing driving and modulatory inputs to be multiplied together. The nonlinearity introduced by STD transforms inhibition-mediated additive shifts in the input-output relationship into multiplicative gain changes. When granule cells were driven with bursts of high-frequency mossy fibre input, as observed in vivo, larger inhibition-mediated gain changes were observed, as expected with greater STD. Simulations of synaptic integration in more complex neocortical neurons suggest that STD-based gain modulation can also operate in neurons with large dendritic trees. Our results establish that neurons receiving depressing excitatory inputs can act as powerful multiplicative devices even when integration of postsynaptic conductances is linear.

Show MeSH
Related in: MedlinePlus