- Email: [email protected]
Serotonergic modulation of the cerebellar granule cell network
Neurocomputing 26}27 (1999) 419}426
Serotonergic modulation of the cerebellar granule cell network夽 Linda J. Larson-Prior *, Huo Lu Department of Basic Sciences, Touro University of Osteopathic Medicine, 1210 Scott Street, San Francisco, CA 94115, USA Division of Biology, California Institute of Technology, USA
Abstract The e!ects of serotonin (5-hydroxytryptamine, 5-HT) on a transient outward potassium current (I ) and on synaptically evoked IPSCs were simulated in a cerebellar granule cell (GC) model that included both feedforward and feedback inhibition. Responses of a GC to synaptic inputs of 10}100 Hz were evaluated. Serotonergic modulation of I reduced the GC "ring rate only at low input frequencies. By its actions on IPSC amplitude, 5-HT was able to reduce GC "ring rate even at higher input frequencies. Thus, the additive e!ect of 5-HT on intrinsic and extrinsic membrane currents e!ectively resets the GC "ring threshold to high-pass "lter the input signal. 1999 Published by Elsevier Science B.V. All rights reserved. Keywords: Serotonin (5-HT); Cerebellar granule cell (GC); Transient potassium current (I ); IPSC; Frequency-dependent information processing
1. Introduction Serotonin (5-HT) has been demonstrated to a!ect neurotransmission in central nervous system areas involved in generating or modulating movement. 5-HT neurons of the raphe and reticular systems project to cerebellum through two distinct systems: a mossy "ber input system which contacts granule cells (GC) in specialized glomeruli
* Corresponding author. E-mail address: [email protected] (L.J. Larson-Prior) 夽 This research was supported by National Institutes of Health (NS 30759) and the National Science Foundation (IBN 9514844) to LLP. 0925-2312/99/$ } see front matter 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 9 2 5 - 2 3 1 2 ( 9 9 ) 0 0 0 4 7 - 8
420
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
and a multilayered system that has been hypothesized to provide both hormonal and synaptic input to all three cerebellar cortical layers [3]. Activation of these input systems modulates spontaneous "ring rates of the cerebellar cortical output neuron [15,16]. The physiological responses of extracellularly recorded cerebellar Purkinje cells (PCs) to exogenously applied 5-HT include both increases and decreases in spontaneous "ring rates [4,7]. 5-HT mediated changes in PC "ring rate have been shown to be at least partially due to the modulation of several potassium channels, including a fast transient potassium conductance (I ) [18]. Cellular and synaptically-evoked responses of intracellularly recorded cerebellar PCs to exogenously applied 5-HT suggest that 5-HT regulates cerebellar output by the modulation of synaptic interactions with GABAergic systems at multiple levels of the cortical network [11,12]. Our recent studies have con"rmed that cellular and synaptic modulation by 5-HT occurs in the GC network as well. Experimentally, 5-HT was demonstrated to enhance I to a maximum of 40% of control value [10]. 5-HT also modulated the IPSC evoked in GCs by white matter stimulation, enhancing IPSC amplitude from 50 to 100% of control value [9]. Our data [13] and that of others [1,14] indicate that this IPSC is GABA receptor-mediated. The GC network receives inputs that vary considerably in frequency, and our experimental [8] and simulation [10] studies suggest that mossy "ber input frequency forms an important parameter in GC output. As the serotonergic system has considerable impact at the level of the GC network, its ability to modulate GC responses to mossy "ber inputs of varying frequency is likely to considerably impact sensory information transmission in the cerebellar cortex.
2. Model implementation We have developed a multi-compartment GC model using GENESIS simulation software (v. 2.1) that includes both excitatory and inhibitory conductances [13]. In this model, feedforward (FF) and feedback (FB) inputs to the simulated GC were implemented as loop time delays of 5 and 8.5 ms, respectively (Fig. 1). The modulatory e!ects of 5-HT on GC responses were simulated as a 40% increase in the I conductance at the somal compartment and a 100% increase in GABA conductance (I ) at the dendritic bulb compartment. FF and FB inhibition were % simulated on di!erent dendrites to prevent saturation of the GABA conductance which our simulations demonstrated to occur when both circuits access the same dendrite (data not shown).
3. Results Serotonergic modulation of GC conductances was implemented as a response to stimuli applied to the dendritic bulb that varied from 10 to 100 Hz in 10 Hz increments. Since 5-HT may or may not a!ect both I and I in a speci"c GC, GC %
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
421
Fig. 1. Schematic of simulation, including the full granule cell model with FF and FB inhibitory loops included. (A) This 59-compartment GC model includes a somal compartment, four dendrites and their dendritic bulbs, and the complete axonal arbor. The length of the PF on either side of the bifurcation was set at 600 lm, which is approximately the size of a single Golgi cell dendritic arbor [1]. (B) Schematic diagram illustrating simulation of FF and FB loops as time delays.
responses were tested under each of the following conditions: no 5-HT a!ect, 5-HT a!ect on I only, 5-HT a!ect on I only and 5-HT e!ect on both I and I . % % 3.1. Response of GC to 5-HT modulation of I
A 40% increase in I results in a 60% reduction in the GC "ring rate only to inputs of 430 Hz (Figs. 2 and 4). At frequencies greater than this (i.e. 100 Hz), a 40% increase in I makes little or no change in the GC output frequency (Figs. 3 and 4). These data suggest that serotonergic modulation of GC responses to MF "ring rates of 430 Hz can be accomplished through direct actions on the GC membrane, but would have little a!ect on inputs of higher frequency. Further, given that I is activatable only on the somal membrane, that paracrine release of 5-HT may have its primary e!ects on MF information transmitted at rates of 430 Hz. 3.2. Response of GC to 5-HT modulation of I
%
The e!ect of a 100% enhancement in IPSC amplitude on the GC response to input "ring rates of 440 Hz is a 40% reduction in output "ring rate (Figs. 2 and 4).
422
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
Fig. 2. Serotonergic e!ects on granule cell "ring rate at a selected low input frequency (10 Hz). (A) Control responses of the GC model with no a!ect of 5-HT. (B) The GC "ring rate decreases in the presence of a 40% increase in I . (C) In the presence of a 100% increase in I , GC "ring rate was also % reduced. (D) Together, a 40% increase in I and a 100% increase in I abolished stimulus-evoked GC % "ring.
However, unlike the GC response to modulation of I , a further 15% reduction in the GC "ring rate was produced in response to higher frequency inputs (Figs. 3 and 4). The activation of GABAergic inputs to the simulated GC occurred only at the dendritic bulb, which has been shown to have a high density of GABA receptors. However, the e!ect of 5-HT on GABAergic transmission, particularly with paracrine release, may be further enhanced by activation of GABA receptors located on the GC somata [2]. 3.3. Additive ewect of 5-HT on GC responses In a functional cerebellar network, release of 5-HT is likely to a!ect both I and I on the same cell. Therefore, the in#uence of both 5-HT e!ects on GC responses % to varying input rates was also tested. In this case, 5-HT acted to shift the GC response to the right, producing a decrement of GC output "ring rate at all tested input frequencies. Functionally, this rightward shift can be interpreted as a resetting of the GC "ring threshold (Figs. 2}4).
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
423
Fig. 3. Serotonin e!ects on granule cell "ring rate at a selected high input frequency (100 Hz). (A) GC response to a 100 Hz input applied at one dendrite with no 5-HT a!ect. (B) A 40% increase in I caused no change in the GC response to a 100 Hz input. (C) A 100% increase in I produced a 15% reduction in % the GC response to a 100 Hz input. (D) Together, a 40% increase in I and a 100% increase in I caused % a 20% reduction in GC "ring rate.
Fig. 4. E!ect of 5-HT across tested input frequency range. The GC output frequency is plotted against stimulation frequency for the following conditions: control (䊐); with a 40% increase in I (䢇); with a 100% increase in I (䉱)and with increases in both I and I (䊏). 5-HT can be seen to a!ect the GC output % % under all conditions tested (see text for details).
424
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
4. Discussion 4.1. 5-HT modulates cellular and synaptic transmission The results of these simulation experiments demonstrate that GC output frequency can be modulated by the actions of 5-HT on two distinct membrane currents: I on the GC soma and dendritically localized I . The e!ect of 5-HT on I is strong only % when the input frequency is less than 30 Hz; inputs of 50 Hz or more are not a!ected. A much stronger modulatory in#uence is mediated by the serotonergic enhancement of GABAergic inhibition which is most e!ective at input frequencies of 50 Hz or more. These data suggest that serotonergic modulation of GC output could act through two di!erent mechanisms when the "ring rates of sensory inputs are in di!erent frequency ranges. If these two systems are accessed di!erently by 5-HT, they could provide a mechanism for preferentially reducing the e$cacy of either low (450 Hz) or high (450) frequency input from the GC to the PC network. An intriguing possibility for di!erential activation of these systems is suggested by the "nding that GABA receptors are located on the synaptically isolated GC soma [2]. This suggests that paracrine release mechanisms might preferentially a!ect I and I at the soma, % while synaptic release of 5-HT largely a!ects dendritic GABA currents. Alternatively, these two systems could act in concert to globally reduce the e$cacy of sensory information transfer from GC to PC network. 4.2. 5-HT may act as a biaser in the cerebellar cortical network A common property of inhibitory synaptic transmission in the central nervous system is a run-down of inhibitory e$cacy [5,6] which was not simulated in these studies. If this e!ect exists in the GC network, the reduction of GC "ring rate caused by serotonergic enhancement of the IPSC may be not as great as was shown in the simulation results. A global reduction of GC "ring rate caused by 5-HT would only occur at the low frequency range, which may explain the di!erential depression of fast and slow EPSPs shown in our intracellular studies of PC responses to 5-HT [11]. Biochemical evidence for presynaptic inhibition of glutamate release from MF terminals via 5-HT receptor activation has been presented [17], and was not implemented in our current simulation studies. We would predict that such an action of 5-HT would result in a further reduction in the GC "ring rate. Therefore, a more global modulatory role of 5-HT may be to balance excitatory and inhibitory drive in the GC network.
5. Conclusion This modeling study suggests that 5-HT may signi"cantly impact frequencydependent information transfer from the GC to PC cerebellar networks. These studies lead to the suggestion that 5-HT may, by release either at the glomerular synapse or by paracrine release a!ecting GC somatic currents, di!erentially modulate GC output
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
425
dependent on the "ring rate of mossy "bers that access that synapse. If 5-HT can modulate cellular and synaptic properties preferentially, it could provide a mechanism for reducing the e$cacy of either low- or high-frequency input from the GC to the PC network. Alternatively, it may act to facilitate the transmission of high-frequency information to the PC network by resetting of the GC "ring threshold.
Acknowledgements We thank C.F. Church for his excellent technical assistance. We also thank Dr. Beeman and Babel group for providing help on the GENESIS simulation package.
References [1] S.G. Brickley, S.G. Cull-Candy, M. Farrant, Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABA receptors, Physiology (London) 497 (Pt 3) (1996) 753}759. [2] H.J. Caruncho, G. Puia, H. Mohler, E. Costa, The density and distribution of six GABA-A receptor subunits in primary cultures of rat cerebellar granule cells, J. Neurosci. 67 (1995) 583}593. [3] V. Chan-Palay, Fine structure of labeled axons in the cerebellar cortex and nuclei of rodents and primates after intraventricular infusions with tritiated serotonin, Anat. Embryol. 148 (1975) 235}265. [4] E.J. Darrow, H.K. Strahlendorf, J.C. Strahlendorf, Response of cerebellar Purkinje cells to serotonin and the 5HT agonists 8-OH-DPAT and ipsapirone in vitro, Eur. J. Pharmacol. 175 (1990) 145}153. [5] M. Gyenes, M. Farrant, D.H. Farb, Run-dwon of gamma-aminobutyric acidA receptor function during whole-cell recording: a possible role for phosphorylation, Mol. Pharmacol. 34 (1988) 719}723. [6] M. Gyenes, Q. Wang, T.T. Gibbs, D.H. Farb, Phosphorylation factors control neurotransmitter and neuromodulator actions at the gamma-aminobutyric acid type A receptor, Mol. Pharmacol. 46 (1994) 542}549. [7] C.W. Kerr, G.A. Bishop, The physiological e!ects of serotonin are mediated by the 5-HT receptor in the cat's cerebellar cortex, Brain Res. 591 (1992) 253}260. [8] L.J. Larson-Prior, Serotonergic modulation of inhibition in the cerebellar granule cell layer, Neurosci. Abstr. 24 (1998) 666. [9] L.J. Larson-Prior, C.F. Church, Response of cerebellar granule cells to synaptic inputs of increasing rate, Neurosci. Abstr. 23 (1997) 1287. [10] H. Lu, L.J. Larson-Prior, E!ects of serotonin on cerebellar granule cell electrical properties, Neurosci. Abstr. 22 (1996) 1627. [11] H. Lu, L.J. Larson-Prior, Serotonergic modulation of evoked responses in turtle cerebellar Purkinje cells, J. Neurophysiol. 76 (5) (1996) 3102}3113. [12] H. Lu, L.J. Larson-Prior, Cellular electrophysiological responses of cerebellar Purkinje cells to serotonin and GABA, Neurosci. Abstr. 23 (1997) 1288. [13] H. Lu, F.W. Prior, L.J. Larson-Prior, The role of feedforward and feedback inhibition on frequencydependent information processing in a cerebellar granule cell, in: J. Bower (Ed.), Computational Neuroscience: Trends in Research' 1998, Plenum Press, New York, 1998. [14] Z. Nusser, W. Sieghart, P. Somogyi, Segregation of di!erent GABA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells, J. Neurosci. 18 (5) (1998) 1693}1703. [15] J.C. Strahlendorf, M. Lee, H.K. Strahlendorf, E!ects of serotonin on cerebellar Purkinje cells are dependent on the baseline "ring rate, Exp. Brain Res. 56 (1984) 50}58.
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L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
[16] J.C. Strahlendorf, M. Lee, H.K. Strahlendorf, Modulatory role of serotonin on GABA-elicited inhibition of cerebellar Purkinje cells, J. Neurosci. 30 (1989) 117}125. [17] S. Thellung, A. Barzizza, G. Maura, M. Raiteri, Serotonergic inhibition of the mossy-"ber-granule cell glutamate transmission in rat cerebellar slices, Naunyn}Schmiedegerg's Arch. Pharmacol. 348 (1993) 347}351. [18] Y. Wang, J.C. Strahlendorf, H.K. Strahlendorf, Serotonin reduces a voltage-dependent transient outward potassium current and enhances excitability of cerebellar Purkinje cells, Brain Res. 571 (1992) 345}349.
Serotonergic modulation of the cerebellar granule cell network夽 Linda J. Larson-Prior *, Huo Lu Department of Basic Sciences, Touro University of Osteopathic Medicine, 1210 Scott Street, San Francisco, CA 94115, USA Division of Biology, California Institute of Technology, USA
Abstract The e!ects of serotonin (5-hydroxytryptamine, 5-HT) on a transient outward potassium current (I ) and on synaptically evoked IPSCs were simulated in a cerebellar granule cell (GC) model that included both feedforward and feedback inhibition. Responses of a GC to synaptic inputs of 10}100 Hz were evaluated. Serotonergic modulation of I reduced the GC "ring rate only at low input frequencies. By its actions on IPSC amplitude, 5-HT was able to reduce GC "ring rate even at higher input frequencies. Thus, the additive e!ect of 5-HT on intrinsic and extrinsic membrane currents e!ectively resets the GC "ring threshold to high-pass "lter the input signal. 1999 Published by Elsevier Science B.V. All rights reserved. Keywords: Serotonin (5-HT); Cerebellar granule cell (GC); Transient potassium current (I ); IPSC; Frequency-dependent information processing
1. Introduction Serotonin (5-HT) has been demonstrated to a!ect neurotransmission in central nervous system areas involved in generating or modulating movement. 5-HT neurons of the raphe and reticular systems project to cerebellum through two distinct systems: a mossy "ber input system which contacts granule cells (GC) in specialized glomeruli
* Corresponding author. E-mail address: [email protected] (L.J. Larson-Prior) 夽 This research was supported by National Institutes of Health (NS 30759) and the National Science Foundation (IBN 9514844) to LLP. 0925-2312/99/$ } see front matter 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 9 2 5 - 2 3 1 2 ( 9 9 ) 0 0 0 4 7 - 8
420
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
and a multilayered system that has been hypothesized to provide both hormonal and synaptic input to all three cerebellar cortical layers [3]. Activation of these input systems modulates spontaneous "ring rates of the cerebellar cortical output neuron [15,16]. The physiological responses of extracellularly recorded cerebellar Purkinje cells (PCs) to exogenously applied 5-HT include both increases and decreases in spontaneous "ring rates [4,7]. 5-HT mediated changes in PC "ring rate have been shown to be at least partially due to the modulation of several potassium channels, including a fast transient potassium conductance (I ) [18]. Cellular and synaptically-evoked responses of intracellularly recorded cerebellar PCs to exogenously applied 5-HT suggest that 5-HT regulates cerebellar output by the modulation of synaptic interactions with GABAergic systems at multiple levels of the cortical network [11,12]. Our recent studies have con"rmed that cellular and synaptic modulation by 5-HT occurs in the GC network as well. Experimentally, 5-HT was demonstrated to enhance I to a maximum of 40% of control value [10]. 5-HT also modulated the IPSC evoked in GCs by white matter stimulation, enhancing IPSC amplitude from 50 to 100% of control value [9]. Our data [13] and that of others [1,14] indicate that this IPSC is GABA receptor-mediated. The GC network receives inputs that vary considerably in frequency, and our experimental [8] and simulation [10] studies suggest that mossy "ber input frequency forms an important parameter in GC output. As the serotonergic system has considerable impact at the level of the GC network, its ability to modulate GC responses to mossy "ber inputs of varying frequency is likely to considerably impact sensory information transmission in the cerebellar cortex.
2. Model implementation We have developed a multi-compartment GC model using GENESIS simulation software (v. 2.1) that includes both excitatory and inhibitory conductances [13]. In this model, feedforward (FF) and feedback (FB) inputs to the simulated GC were implemented as loop time delays of 5 and 8.5 ms, respectively (Fig. 1). The modulatory e!ects of 5-HT on GC responses were simulated as a 40% increase in the I conductance at the somal compartment and a 100% increase in GABA conductance (I ) at the dendritic bulb compartment. FF and FB inhibition were % simulated on di!erent dendrites to prevent saturation of the GABA conductance which our simulations demonstrated to occur when both circuits access the same dendrite (data not shown).
3. Results Serotonergic modulation of GC conductances was implemented as a response to stimuli applied to the dendritic bulb that varied from 10 to 100 Hz in 10 Hz increments. Since 5-HT may or may not a!ect both I and I in a speci"c GC, GC %
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
421
Fig. 1. Schematic of simulation, including the full granule cell model with FF and FB inhibitory loops included. (A) This 59-compartment GC model includes a somal compartment, four dendrites and their dendritic bulbs, and the complete axonal arbor. The length of the PF on either side of the bifurcation was set at 600 lm, which is approximately the size of a single Golgi cell dendritic arbor [1]. (B) Schematic diagram illustrating simulation of FF and FB loops as time delays.
responses were tested under each of the following conditions: no 5-HT a!ect, 5-HT a!ect on I only, 5-HT a!ect on I only and 5-HT e!ect on both I and I . % % 3.1. Response of GC to 5-HT modulation of I
A 40% increase in I results in a 60% reduction in the GC "ring rate only to inputs of 430 Hz (Figs. 2 and 4). At frequencies greater than this (i.e. 100 Hz), a 40% increase in I makes little or no change in the GC output frequency (Figs. 3 and 4). These data suggest that serotonergic modulation of GC responses to MF "ring rates of 430 Hz can be accomplished through direct actions on the GC membrane, but would have little a!ect on inputs of higher frequency. Further, given that I is activatable only on the somal membrane, that paracrine release of 5-HT may have its primary e!ects on MF information transmitted at rates of 430 Hz. 3.2. Response of GC to 5-HT modulation of I
%
The e!ect of a 100% enhancement in IPSC amplitude on the GC response to input "ring rates of 440 Hz is a 40% reduction in output "ring rate (Figs. 2 and 4).
422
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
Fig. 2. Serotonergic e!ects on granule cell "ring rate at a selected low input frequency (10 Hz). (A) Control responses of the GC model with no a!ect of 5-HT. (B) The GC "ring rate decreases in the presence of a 40% increase in I . (C) In the presence of a 100% increase in I , GC "ring rate was also % reduced. (D) Together, a 40% increase in I and a 100% increase in I abolished stimulus-evoked GC % "ring.
However, unlike the GC response to modulation of I , a further 15% reduction in the GC "ring rate was produced in response to higher frequency inputs (Figs. 3 and 4). The activation of GABAergic inputs to the simulated GC occurred only at the dendritic bulb, which has been shown to have a high density of GABA receptors. However, the e!ect of 5-HT on GABAergic transmission, particularly with paracrine release, may be further enhanced by activation of GABA receptors located on the GC somata [2]. 3.3. Additive ewect of 5-HT on GC responses In a functional cerebellar network, release of 5-HT is likely to a!ect both I and I on the same cell. Therefore, the in#uence of both 5-HT e!ects on GC responses % to varying input rates was also tested. In this case, 5-HT acted to shift the GC response to the right, producing a decrement of GC output "ring rate at all tested input frequencies. Functionally, this rightward shift can be interpreted as a resetting of the GC "ring threshold (Figs. 2}4).
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
423
Fig. 3. Serotonin e!ects on granule cell "ring rate at a selected high input frequency (100 Hz). (A) GC response to a 100 Hz input applied at one dendrite with no 5-HT a!ect. (B) A 40% increase in I caused no change in the GC response to a 100 Hz input. (C) A 100% increase in I produced a 15% reduction in % the GC response to a 100 Hz input. (D) Together, a 40% increase in I and a 100% increase in I caused % a 20% reduction in GC "ring rate.
Fig. 4. E!ect of 5-HT across tested input frequency range. The GC output frequency is plotted against stimulation frequency for the following conditions: control (䊐); with a 40% increase in I (䢇); with a 100% increase in I (䉱)and with increases in both I and I (䊏). 5-HT can be seen to a!ect the GC output % % under all conditions tested (see text for details).
424
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
4. Discussion 4.1. 5-HT modulates cellular and synaptic transmission The results of these simulation experiments demonstrate that GC output frequency can be modulated by the actions of 5-HT on two distinct membrane currents: I on the GC soma and dendritically localized I . The e!ect of 5-HT on I is strong only % when the input frequency is less than 30 Hz; inputs of 50 Hz or more are not a!ected. A much stronger modulatory in#uence is mediated by the serotonergic enhancement of GABAergic inhibition which is most e!ective at input frequencies of 50 Hz or more. These data suggest that serotonergic modulation of GC output could act through two di!erent mechanisms when the "ring rates of sensory inputs are in di!erent frequency ranges. If these two systems are accessed di!erently by 5-HT, they could provide a mechanism for preferentially reducing the e$cacy of either low (450 Hz) or high (450) frequency input from the GC to the PC network. An intriguing possibility for di!erential activation of these systems is suggested by the "nding that GABA receptors are located on the synaptically isolated GC soma [2]. This suggests that paracrine release mechanisms might preferentially a!ect I and I at the soma, % while synaptic release of 5-HT largely a!ects dendritic GABA currents. Alternatively, these two systems could act in concert to globally reduce the e$cacy of sensory information transfer from GC to PC network. 4.2. 5-HT may act as a biaser in the cerebellar cortical network A common property of inhibitory synaptic transmission in the central nervous system is a run-down of inhibitory e$cacy [5,6] which was not simulated in these studies. If this e!ect exists in the GC network, the reduction of GC "ring rate caused by serotonergic enhancement of the IPSC may be not as great as was shown in the simulation results. A global reduction of GC "ring rate caused by 5-HT would only occur at the low frequency range, which may explain the di!erential depression of fast and slow EPSPs shown in our intracellular studies of PC responses to 5-HT [11]. Biochemical evidence for presynaptic inhibition of glutamate release from MF terminals via 5-HT receptor activation has been presented [17], and was not implemented in our current simulation studies. We would predict that such an action of 5-HT would result in a further reduction in the GC "ring rate. Therefore, a more global modulatory role of 5-HT may be to balance excitatory and inhibitory drive in the GC network.
5. Conclusion This modeling study suggests that 5-HT may signi"cantly impact frequencydependent information transfer from the GC to PC cerebellar networks. These studies lead to the suggestion that 5-HT may, by release either at the glomerular synapse or by paracrine release a!ecting GC somatic currents, di!erentially modulate GC output
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
425
dependent on the "ring rate of mossy "bers that access that synapse. If 5-HT can modulate cellular and synaptic properties preferentially, it could provide a mechanism for reducing the e$cacy of either low- or high-frequency input from the GC to the PC network. Alternatively, it may act to facilitate the transmission of high-frequency information to the PC network by resetting of the GC "ring threshold.
Acknowledgements We thank C.F. Church for his excellent technical assistance. We also thank Dr. Beeman and Babel group for providing help on the GENESIS simulation package.
References [1] S.G. Brickley, S.G. Cull-Candy, M. Farrant, Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABA receptors, Physiology (London) 497 (Pt 3) (1996) 753}759. [2] H.J. Caruncho, G. Puia, H. Mohler, E. Costa, The density and distribution of six GABA-A receptor subunits in primary cultures of rat cerebellar granule cells, J. Neurosci. 67 (1995) 583}593. [3] V. Chan-Palay, Fine structure of labeled axons in the cerebellar cortex and nuclei of rodents and primates after intraventricular infusions with tritiated serotonin, Anat. Embryol. 148 (1975) 235}265. [4] E.J. Darrow, H.K. Strahlendorf, J.C. Strahlendorf, Response of cerebellar Purkinje cells to serotonin and the 5HT agonists 8-OH-DPAT and ipsapirone in vitro, Eur. J. Pharmacol. 175 (1990) 145}153. [5] M. Gyenes, M. Farrant, D.H. Farb, Run-dwon of gamma-aminobutyric acidA receptor function during whole-cell recording: a possible role for phosphorylation, Mol. Pharmacol. 34 (1988) 719}723. [6] M. Gyenes, Q. Wang, T.T. Gibbs, D.H. Farb, Phosphorylation factors control neurotransmitter and neuromodulator actions at the gamma-aminobutyric acid type A receptor, Mol. Pharmacol. 46 (1994) 542}549. [7] C.W. Kerr, G.A. Bishop, The physiological e!ects of serotonin are mediated by the 5-HT receptor in the cat's cerebellar cortex, Brain Res. 591 (1992) 253}260. [8] L.J. Larson-Prior, Serotonergic modulation of inhibition in the cerebellar granule cell layer, Neurosci. Abstr. 24 (1998) 666. [9] L.J. Larson-Prior, C.F. Church, Response of cerebellar granule cells to synaptic inputs of increasing rate, Neurosci. Abstr. 23 (1997) 1287. [10] H. Lu, L.J. Larson-Prior, E!ects of serotonin on cerebellar granule cell electrical properties, Neurosci. Abstr. 22 (1996) 1627. [11] H. Lu, L.J. Larson-Prior, Serotonergic modulation of evoked responses in turtle cerebellar Purkinje cells, J. Neurophysiol. 76 (5) (1996) 3102}3113. [12] H. Lu, L.J. Larson-Prior, Cellular electrophysiological responses of cerebellar Purkinje cells to serotonin and GABA, Neurosci. Abstr. 23 (1997) 1288. [13] H. Lu, F.W. Prior, L.J. Larson-Prior, The role of feedforward and feedback inhibition on frequencydependent information processing in a cerebellar granule cell, in: J. Bower (Ed.), Computational Neuroscience: Trends in Research' 1998, Plenum Press, New York, 1998. [14] Z. Nusser, W. Sieghart, P. Somogyi, Segregation of di!erent GABA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells, J. Neurosci. 18 (5) (1998) 1693}1703. [15] J.C. Strahlendorf, M. Lee, H.K. Strahlendorf, E!ects of serotonin on cerebellar Purkinje cells are dependent on the baseline "ring rate, Exp. Brain Res. 56 (1984) 50}58.
426
L.J. Larson-Prior, H. Lu / Neurocomputing 26}27 (1999) 419}426
[16] J.C. Strahlendorf, M. Lee, H.K. Strahlendorf, Modulatory role of serotonin on GABA-elicited inhibition of cerebellar Purkinje cells, J. Neurosci. 30 (1989) 117}125. [17] S. Thellung, A. Barzizza, G. Maura, M. Raiteri, Serotonergic inhibition of the mossy-"ber-granule cell glutamate transmission in rat cerebellar slices, Naunyn}Schmiedegerg's Arch. Pharmacol. 348 (1993) 347}351. [18] Y. Wang, J.C. Strahlendorf, H.K. Strahlendorf, Serotonin reduces a voltage-dependent transient outward potassium current and enhances excitability of cerebellar Purkinje cells, Brain Res. 571 (1992) 345}349.