The stomatogastric ganglion of the crab, Cancer borealis, is modulated by Ͼ20 different substances, including numerous neuropeptides. One of these peptides, proctolin, activates an inward current that shows strong outward rectification (Golowasch and Marder, 1992). Decreasing the extracellular Ca 2ϩ concentration linearizes the current-voltage curve of the proctolin-induced current. We used voltage clamp to study the currents evoked by proctolin and five additional modulators [C. borealis tachykinin-related peptide Ia (CabTRP Ia), crustacean cardioactive peptide, red pigment-concentrating hormone, TNRNFLRFamide, and the muscarinic agonist pilocarpine] in stomatogastric ganglion neurons, both in the intact ganglion and in dissociated cell culture. Subtraction currents yielded proctolinlike current-voltage relationships for all six substances, and the current-voltage curves of all six substances showed linearization in low external Ca 2ϩ . The lateral pyloric neuron responded to all six modulators, but the ventricular dilator neuron only responded to a subset of them. Bath application of saturating concentrations of proctolin occluded the response to CabTRP and vice versa. N-(6-Aminohexyl)-5-chloro-1-napthalensulfonamide, a calmodulin inhibitor, increased the amplitude and altered the voltage dependence of the responses elicited by CabTRP and proctolin. Together, these data indicate that all six substances converge onto the same voltage-dependent current, although they activate different receptors. Therefore, differential network responses evoked by these substances may primarily depend on the receptor distribution on network neurons.Key words: stomatogastric ganglion; crab; Cancer borealis; proctolin; CCAP; RPCH; crab tachykinin-related peptide; FLRFamide-related peptides Nervous systems contain many neuropeptides and amines that modulate synaptic strength and cellular excitability (Nicoll et al., 1990;Kupfermann, 1991;Marder and Calabrese, 1996;Marder, 1998). Most voltage-dependent ion channels are subject to modulation by one or more substances, and many agonists modulate multiple membrane currents (Kaczmarek and Levitan, 1987;Levitan, 1988Levitan, , 1994 Hille, 1992Hille, , 1994Gudermann et al., 1997). In principle, the large number of different intrinsic and synaptic currents subject to modulation could provide the potential substrate for virtually infinite modifications of circuit behavior under different modulatory conditions. Nonetheless, there are numerous examples of convergent actions of modulators, in which several substances act on the same current (Dunlap and Fischbach, 1978;Jones, 1985;Christie and North, 1988;Nicoll et al., 1990;Bolshakov et al., 1993; Brezina et al., 1994a,b;van Tol-Steye et al., 1997;Sodickson and Bean, 1998). Convergent actions of modulators may appear to be redundant at the level of the single neuron but may not be redundant at the level of network behavior, if different substances activate different receptors on separate populations of target neurons.The crustacean stomatogast...
Cerebellar Purkinje neurons have intrinsic membrane properties that favor burst firing, seen not only during complex spikes elicited by climbing fiber input but also with direct electrical stimulation of cell bodies. We examined the ionic conductances that underlie all-ornone burst firing elicited in acutely dissociated mouse Purkinje neurons by short depolarizing current injections. Blocking voltagedependent calcium entry by cadmium or replacement of external calcium by magnesium enhanced burst firing, but it was blocked by cobalt replacement of calcium, probably reflecting block of sodium channels. In voltage-clamp experiments, we used the burst waveform of each cell as a voltage command and used ionic substitutions and pharmacological manipulations to isolate tetrodotoxin (TTX)-sensitive sodium current, P-type and T-type calcium current, hyperpolarization-activated cation current (I h ), voltage-activated potassium current, large-conductance calcium-activated potassium current, and small-conductance calcium-activated potassium (SK) current. Measured near the middle of the first interspike interval, TTX-sensitive sodium current carried the largest inward current, and T-type calcium current was also substantial. Current through P-type channels was large immediately after a spike but decayed rapidly. These inward currents were opposed by substantial components of voltage-dependent and calcium-dependent potassium current. Termination of the burst is caused partly by decay of sodium current, together with a progressive buildup of SK current after the first interspike interval. Although burst firing depends on the net balance between multiple large currents flowing after a spike, it is surprisingly robust, probably reflecting complex interactions between the exact voltage waveform and voltage and calcium dependence of the various currents.
Cerebellar Purkinje neurons often generate all-or-none burst firing in response to depolarizing stimuli. Voltage-clamp experiments using action potential waveforms show that burst firing depends on small net inward currents that flow after spikes and reflect the net balance between multiple large currents. Given this, burst firing is surprisingly robust in the face of changes in the magnitude of the underlying currents from cell to cell. We explored the basis of this robustness by examining the effects of reducing the sodium current, the major contributor to the postspike inward current. Burst firing persisted in concentrations of tetrodotoxin that produced half-block of sodium current. This robustness of bursting reflects an acute feedback mechanism whereby waveform changes from the reduced sodium current (reduced spike height and a hyperpolarizing shift in postspike voltage) cause compensatory decreases in postspike potassium currents. In particular, reduced spike height reduces calcium entry and subsequent calcium-activated potassium current, and the hyperpolarizing shift in postspike voltage speeds deactivation of Kv3-like potassium channels. Other experiments examined bursting in Na v 1.6 Ϫ/Ϫ mice, in which sodium current density is reduced in the long term. Under these circumstances, there was upregulation of both T-type and P-type calcium current and a change in the balance of calcium current and calcium-activated potassium current such that their net influence shifted from being inhibitory during bursts in wild-type neurons to excitatory during bursts from Na v 1.6 Ϫ/Ϫ mutant neurons. Thus, Purkinje neurons have both acute and long-term feedback mechanisms that serve to maintain burst firing when voltage-dependent sodium conductance is reduced.
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