Synaptic integration in a model of cerebellar granule cells

Abstract

1. We have developed a compartmental model of a turtle cerebellar granule cell consisting of 13 compartments that represent the soma and 4 dendrites. We used this model to investigate the synaptic integration of mossy fiber inputs in granule cells. 2. The somatic compartment contained six active ionic conductances: a sodium conductance with fast activation and inactivation kinetics, gNa; a high-voltage-activated calcium conductance, gCa(HVA); a delayed potassium conductance, gK(DR); a transient potassium conductance, gK(A); a slowly relaxing mixed Na+/K+ conductance activating at hyperpolarized membrane potentials, gH, and a calcium- and voltage-dependent potassium conductance, gK(Ca). The kinetics of these conductances was derived from electrophysiological studies in a variety of preparations, including turtle and rat granule cells. 3. In the soma, dynamics of intracellular free Ca2+ was modeled by incorporation of a Na+/Ca2+ exchanger, radial diffusion, and binding sites for Ca2+. 4. The model of the turtle granule cell exhibited depolarization-induced action potential firing with properties closely resembling those seen with intracellular recordings in turtle granule cells in vitro. 5. In the most distal compartments of the dendrites, mossy fiber activity induced synaptic currents mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)- and N-methyl-D-aspartate (NMDA)-type of glutamate receptors. The strength of synaptic inputs chosen was such that the synaptic potential induced by synchronous activation of two mossy fiber synapses reached threshold for induction of a single action potential. 6. The slow time course of the NMDA synaptic current together with the slow relaxation kinetics of gH significantly affected the temporal summation of excitatory synaptic potentials. A priming action potential evoked by mossy fiber stimulation increased the maximal time interval between two synaptic potentials capable to reach again threshold for a subsequent action potential. This time interval then decreased in parallel with the decay of the NMDA synaptic current, reached a minimum after 200 ms, and slowly recovered with reactivation of gH. 7. Repetitive, steady activation of synaptic conductances by a single mossy fiber at different frequencies induced action potential firing with a sharp threshold at 12 Hz. Activity of a single or of several mossy fibers induced firing of the granule cell at a frequency close to that induced when the average synaptic current was directly injected into the cell. The mossy fiber activity-granule cell firing frequency curve was close to linear with a slope of about one-half for input frequencies < or = 400 Hz.(ABSTRACT TRUNCATED AT 400 WORDS)

Synaptic Vesicle Recycling in Cultured Cerebellar Granule Cells: Role of Vesicular Acidification and Refilling

“…Granule cells can be induced to fire at frequencies up to 200 Hz in slice preparations (Gabbiani et al, 1994), and in the present study no depletion in the amount of transmitter release is observed with repetitive trains of stimuli (Fig. 5).…”

Outwardly Rectifying Tonically Active GABAAReceptors in Pyramidal Cells Modulate Neuronal Offset, Not Gain

“…Because the time-averaged voltage in a firing neuron remains approximately constant (close to threshold potential), introducing a shunting conductance results in constant-current offset. This has been confirmed theoretically (Gabbiani et al, 1994;Holt and Koch, 1997) and experimentally with excitation mimicked by constant-current injection (Brickley et al, 1996;Chance et al, 2002;Ulrich, 2003). However, in vivo, neurons are bombarded by a noisy, stochastic input (Paré et al, 1998;Destexhe and Paré, 1999;Destexhe et al, 2001), which influences I-O gain and increases the input range of a neuron (Hô and Destexhe, 2000;Doiron et al, 2001;Chance et al, 2002;Fellous et al, 2003;Wolfart et al, 2005;Higgs et al, 2006).…”

Clustering of Extrasynaptic GABAA Receptors Modulates Tonic Inhibition in Cultured Hippocampal Neurons

“…Since clustered extrasynaptic GABA A receptors mediate larger tonic currents, it is possible that, under either physiological or pathological conditions, receptor clustering can modulate tonic inhibition and in turn influence synaptic efficacy and integration (6,10,13,14,20).…”

“…Whereas synaptic GABA A receptors are involved in phasic inhibition (1), extrasynaptic ones are responsible for tonic inhibition (2)(3)(4)(5)(6)(7)(8)(9). Tonic inhibition is due to persistent inhibitory conductance that contributes to "signal integration" in the brain since it sets the threshold for action potential generation (10,11) and shunts excitatory synaptic inputs (2,(12)(13)(14)(15). This conductance is maintained by "ambient" GABA, which represents the amount of neurotransmitter present in the extracellular space.…”