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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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Synaptic depression enhances inhibition-mediated gain modulationa, Hypothetical neuronal input-output relation before (black) and after multiplicative gain modulation (green, ×) and an additive offset (orange, +).b, Averaged AMPAR-mediated synaptic train exhibiting STD (blue trace) in response to Poisson stimulation (black ticks; f = 86 Hz) of single MF inputs. Red trace shows corresponding artificial synaptic train without STD.c, The sum of 4 independent synaptic trains (each f = 86 Hz) with and without STD injected into a GC via dynamic clamp (Gclamp) with and without tonic inhibition (black and gray; Ginh = 500 pS). Right vertical ticks indicate spike times. Horizontal bars indicate output rate measurement window. Vrest = −79 mV.d, Average input-output relations (n = 9) with and without STD (blue and red) and tonic inhibition (open and closed symbols). Lines are fits to a Hill function (Eq. 5; Supplementary Table 1).e, Gain (green) and offset (orange) changes due to STD (±STD) and inhibition (±inh) from fits in d.
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Figure 1: Synaptic depression enhances inhibition-mediated gain modulationa, Hypothetical neuronal input-output relation before (black) and after multiplicative gain modulation (green, ×) and an additive offset (orange, +).b, Averaged AMPAR-mediated synaptic train exhibiting STD (blue trace) in response to Poisson stimulation (black ticks; f = 86 Hz) of single MF inputs. Red trace shows corresponding artificial synaptic train without STD.c, The sum of 4 independent synaptic trains (each f = 86 Hz) with and without STD injected into a GC via dynamic clamp (Gclamp) with and without tonic inhibition (black and gray; Ginh = 500 pS). Right vertical ticks indicate spike times. Horizontal bars indicate output rate measurement window. Vrest = −79 mV.d, Average input-output relations (n = 9) with and without STD (blue and red) and tonic inhibition (open and closed symbols). Lines are fits to a Hill function (Eq. 5; Supplementary Table 1).e, Gain (green) and offset (orange) changes due to STD (±STD) and inhibition (±inh) from fits in d.

Mentions: The way a neuron transforms signals can be captured by its input-output relation (Fig. 1a). A modulatory input can change the shape of this relation, thereby performing a mathematical operation on this transfer function. A shift along the input axis corresponds to an additive operation (+), while a change in slope corresponds to a multiplicative operation, or gain change (×). Cerebellar GCs are well suited for studying gain modulation because they have few synaptic inputs. Excitation comes from ~4 MFs, which can sustain rate-coded signals over a large bandwidth20 and exhibit STD19,21. Inhibition comes from Golgi cells, most of which is mediated by a modulatable tonic GABAA receptor (GABAR) conductance22. Since it is difficult to activate multiple inputs independently, and since we wanted to compare real synaptic inputs exhibiting frequency-dependent STD with artificial synaptic inputs without STD, we used dynamic-clamp to study synaptic integration. GCs are ideal for this because their soma and dendrites form a single electrical compartment, allowing dendritic inputs to be mimicked by somatic conductance injection13.


Synaptic depression enables neuronal gain control.

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

Synaptic depression enhances inhibition-mediated gain modulationa, Hypothetical neuronal input-output relation before (black) and after multiplicative gain modulation (green, ×) and an additive offset (orange, +).b, Averaged AMPAR-mediated synaptic train exhibiting STD (blue trace) in response to Poisson stimulation (black ticks; f = 86 Hz) of single MF inputs. Red trace shows corresponding artificial synaptic train without STD.c, The sum of 4 independent synaptic trains (each f = 86 Hz) with and without STD injected into a GC via dynamic clamp (Gclamp) with and without tonic inhibition (black and gray; Ginh = 500 pS). Right vertical ticks indicate spike times. Horizontal bars indicate output rate measurement window. Vrest = −79 mV.d, Average input-output relations (n = 9) with and without STD (blue and red) and tonic inhibition (open and closed symbols). Lines are fits to a Hill function (Eq. 5; Supplementary Table 1).e, Gain (green) and offset (orange) changes due to STD (±STD) and inhibition (±inh) from fits in d.
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getmorefigures.php?uid=PMC2689940&req=5

Figure 1: Synaptic depression enhances inhibition-mediated gain modulationa, Hypothetical neuronal input-output relation before (black) and after multiplicative gain modulation (green, ×) and an additive offset (orange, +).b, Averaged AMPAR-mediated synaptic train exhibiting STD (blue trace) in response to Poisson stimulation (black ticks; f = 86 Hz) of single MF inputs. Red trace shows corresponding artificial synaptic train without STD.c, The sum of 4 independent synaptic trains (each f = 86 Hz) with and without STD injected into a GC via dynamic clamp (Gclamp) with and without tonic inhibition (black and gray; Ginh = 500 pS). Right vertical ticks indicate spike times. Horizontal bars indicate output rate measurement window. Vrest = −79 mV.d, Average input-output relations (n = 9) with and without STD (blue and red) and tonic inhibition (open and closed symbols). Lines are fits to a Hill function (Eq. 5; Supplementary Table 1).e, Gain (green) and offset (orange) changes due to STD (±STD) and inhibition (±inh) from fits in d.
Mentions: The way a neuron transforms signals can be captured by its input-output relation (Fig. 1a). A modulatory input can change the shape of this relation, thereby performing a mathematical operation on this transfer function. A shift along the input axis corresponds to an additive operation (+), while a change in slope corresponds to a multiplicative operation, or gain change (×). Cerebellar GCs are well suited for studying gain modulation because they have few synaptic inputs. Excitation comes from ~4 MFs, which can sustain rate-coded signals over a large bandwidth20 and exhibit STD19,21. Inhibition comes from Golgi cells, most of which is mediated by a modulatable tonic GABAA receptor (GABAR) conductance22. Since it is difficult to activate multiple inputs independently, and since we wanted to compare real synaptic inputs exhibiting frequency-dependent STD with artificial synaptic inputs without STD, we used dynamic-clamp to study synaptic integration. GCs are ideal for this because their soma and dendrites form a single electrical compartment, allowing dendritic inputs to be mimicked by somatic conductance injection13.

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