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Laurence O Trussell

Publications and source records attributed to Laurence O Trussell.

10 recordsLinked to original sources
PubMed2006

Estimate of the chloride concentration in a central glutamatergic terminal: a gramicidin perforated-patch study on the calyx of Held.

The function of presynaptic terminals is regulated by intracellular Cl-, the levels of which modify vesicular endocytosis and transmitter refilling and mediate the effects of presynaptic ligand-gated Cl- channels. Nevertheless, the concentration of Cl- in a central nerve terminal is unknown, and it is unclear whether terminals can regulate Cl- independently of the soma. Using perforated-patch recording in a mammalian synapse, we found that terminals accumulate Cl- up to 21 mm, between four and five times higher than in their parent cell bodies. Changing [Cl-] did not alter vesicular glutamate content in intact terminals, unlike in vitro experiments. Thus, glutamatergic terminals maintain an elevated Cl- concentration without compromising synaptic transmission.

Action Potentials↗
PubMed2006

Activation and deactivation of voltage-dependent K+ channels during synaptically driven action potentials in the MNTB.

K+ channels shape individual action potentials and determine their pattern of firing. In auditory relays, both high- and low-voltage-activated K+ channels (HVA and LVA) are critical for preservation of auditory timing cues. We examined how these channels participate in firing in the medial nucleus of the trapezoid body. Principal cells at physiological temperature were voltage clamped using spike waveforms previously recorded in response to calyceal firing. Current components were isolated by digital subtraction of traces recorded in the channel antagonists dendrotoxin-I or tetraethylammonium. During orthodromic spikes delivered at 300 and 600 Hz, both currents activated with a slight delay, peaking just after the crest of the spike. The decay of HVA was sufficiently fast to match the time course of the spike. By contrast, with 300-Hz stimuli, LVA continued to decay after the spikes reached a stable interspike potential. Although LVA currents partially inactivate during prolonged voltage steps, their peak amplitudes remained stable or increased during trains of spikelike stimuli. At 600 Hz, LVA did not fully deactivate between the spikes and therefore generated a leak current. To determine the effect of blocking LVA channels on spiking, prerecorded postsynaptic conductances were injected, with and without dendrotoxin-I. After block of LVA channels, strong synaptic conductances produced broader spikes, greater spike jitter, and prolonged depolarized states. HVA blockade with tetraethylammonium also broadened spikes but led to less error in timing. These results reveal multiple roles for LVA channels in spike repolarization and timing during synaptic activity.

Action Potentials↗
PubMed2005

Modulation of transmitter release by presynaptic resting potential and background calcium levels.

Activation of presynaptic ion channels alters the membrane potential of nerve terminals, leading to changes in transmitter release. To study the relationship between resting potential and exocytosis, we combined pre- and postsynaptic electrophysiological recordings with presynaptic Ca(2+) measurements at the calyx of Held. Depolarization of the membrane potential to between -60 mV and -65 mV elicited P/Q-type Ca(2+) currents of < 1 pA and increased intraterminal Ca(2+) by < 100 nM. These small Ca(2+) elevations were sufficient to enhance the probability of transmitter release up to 2-fold, with no effect on the readily releasable pool of vesicles. Moreover, the effects of mild depolarization on release had slow kinetics and were abolished by 1 mM intraterminal EGTA, suggesting that Ca(2+) acted through a high-affinity binding site. Together, these studies suggest that control of resting potential is a powerful means for regulating synaptic function at mammalian synapses.

Agatoxins↗
PubMed2004

Staggered development of GABAergic and glycinergic transmission in the MNTB.

Maturation of some brain stem and spinal inhibitory systems is characterized by a shift from GABAergic to glycinergic transmission. Little is known about how this transition is expressed in terms of individual axonal inputs and synaptic sites. We have explored this issue in the rat medial nucleus of the trapezoid body (MNTB). Synaptic responses at postnatal days 5-7 (P5-P7) were small, slow, and primarily mediated by GABA(A) receptors. By P8-P12, an additional, faster glycinergic component emerged. At these ages, GABA(A), glycine, or both types of receptors mediated transmission, even at single synaptic sites. Thereafter, glycinergic development greatly accelerated. By P25, evoked inhibitory postsynaptic currents (IPSCs) were 10 times briefer and 100 times larger than those measured in the youngest group, suggesting a proliferation of synaptic inputs activating fast-kinetic receptors. Glycinergic miniature IPSCs (mIPSCs) increased markedly in size and decay rate with age. GABAergic mIPSCs also accelerated, but declined slightly in amplitude. Overall, the efficacy of GABAergic inputs showed little maturation between P5 and P20. Although gramicidin perforated-patch recordings revealed that GABA or glycine depolarized P5-P7 cells but hyperpolarized P14-P15 cells, the young depolarizing inputs were not suprathreshold. In addition, vesicle-release properties of inhibitory axons also matured: GABAergic responses in immature rats were highly asynchronous, while in older rats, precise, phasic glycinergic IPSCs could transmit even with 500-Hz stimuli. Thus development of inhibition is characterized by coordinated modifications to transmitter systems, vesicle release kinetics, Cl- gradients, receptor properties, and numbers of synaptic inputs. The apparent switch in GABA/glycine transmission was predominantly due to enhanced glycinergic function.

Age Factors↗
PubMed2004

Cell-specific, spike timing-dependent plasticities in the dorsal cochlear nucleus.

In the dorsal cochlear nucleus, long-term synaptic plasticity can be induced at the parallel fiber inputs that synapse onto both fusiform principal neurons and cartwheel feedforward inhibitory interneurons. Here we report that in mouse fusiform cells, spikes evoked 5 ms after parallel-fiber excitatory postsynaptic potentials (EPSPs) led to long-term potentiation (LTP), whereas spikes evoked 5 ms before EPSPs led to long-term depression (LTD) of the synapse. The EPSP-spike protocol led to LTD in cartwheel cells, but no synaptic changes resulted from the reverse sequence (spike-EPSP). Plasticity in fusiform and cartwheel cells therefore followed Hebbian and anti-Hebbian learning rules, respectively. Similarly, spikes generated by summing EPSPs from different groups of parallel fibers produced LTP in fusiform cells, and LTD in cartwheel cells. LTD could also be induced in glutamatergic inputs of cartwheel cells by pairing parallel-fiber EPSPs with depolarizing glycinergic PSPs from neighboring cartwheel cells. Thus, synaptic learning rules vary with the postsynaptic cell, and may require the interaction of different transmitter systems.

Animals↗
PubMed2004

Inhibitory control at a synaptic relay.

The mammalian medial nucleus of the trapezoid body (MNTB) harbors one of the most powerful terminals in the CNS, the calyx of Held. The mechanisms known to regulate this synaptic relay are relatively ineffective. Here, we report the presence of a remarkably robust and fast-acting glycinergic inhibitory system capable of suppressing calyceal transmission. Evoked glycinergic IPSCs were relatively small in 2-week-old rats, an age by which calyceal maturation has reportedly neared completion. However, by postnatal day 25 (P25), glycinergic transmission had undergone a vigorous transformation, resulting in peak synaptic conductances as high as 280 nS. These are comparable with glutamatergic conductances activated by calyceal inputs. Decay kinetics for IPSCs were severalfold faster than for glycinergic synaptic events reported previously. At physiological temperatures in P25 rats, IPSCs decayed in approximately 1 msec and could be elicited at frequencies up to 500 Hz. Moreover, EPSPs triggered by glutamatergic signals derived from the calyx or simulated by conductance clamp were suppressed when preceded by simulated glycinergic IPSPs. The matching of excitatory transmission in the calyx of Held by a powerful, precision inhibitory system suggests that the relay function of the MNTB may be rapidly modified during sound localization.

Animals↗
PubMed2003

The mechanism of action of aniracetam at synaptic alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors: indirect and direct effects on desensitization.

The mechanism of action of aniracetam on alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors was examined in outside-out patches and at glutamatergic synapses in neurons of the chick cochlear nucleus. A combination of rapid-flow analysis, using glutamate as an agonist, and kinetic modeling indicated that aniracetam slows both the rate of channel closing, and the microscopic rates of desensitization, even for partially liganded receptors. Little effect was observed on the rate of recovery from desensitization or on the response to the weakly desensitizing agonist kainate. Aniracetam's effects on receptor deactivation saturated at lower concentrations than its effects on desensitization, suggesting that cooperativity between homologous binding sites was required to regulate desensitization. Analysis of responses to paired pulses of agonist also indicated that AMPA receptors must desensitize partially even after agonist exposures too brief to permit rebinding. In the presence of aniracetam, evoked excitatory synaptic currents (EPSCs) and miniature EPSCs in low quantal-content conditions had decay times similar to the time course of receptor deactivation. Under these conditions, the time course of both transmitter release and clearance must be <1 to 2 ms. However, in high quantal-content conditions, the evoked EPSC in aniracetam decayed with a time course intermediate between deactivation and desensitization, suggesting that the time course of transmitter clearance is prolonged because of pooling of transmitter in the synaptic cleft. Moreover, by comparing the amounts of paired-pulse synaptic depression and patch desensitization prevented by aniracetam, we conclude that significant desensitization occurs in response to rebinding of transmitter to the AMPA receptors.

Animals↗
PubMed2002

Reciprocal developmental regulation of presynaptic ionotropic receptors.

Activation of ionotropic glycine receptors potentiates glutamate release in mature calyceal nerve terminals of the rat medial nucleus of the trapezoid body, an auditory brainstem nucleus. In young rats, glycine and its receptors are poorly expressed. We therefore asked whether GABA (gamma-aminobutyric acid) might play a larger role than glycine in the regulation of glutamate release in the absence of glycine receptors. Indeed, in rats younger than postnatal day 11 (P11), and before the onset of hearing, calyces expressed high levels of ionotropic GABA(A) receptors but few glycine receptors. Isoguvacine, a selective agonist at GABA(A) receptors, strongly enhanced excitatory postsynaptic currents in young rats but had little effect in rats older than P11. Down-regulation of presynaptic GABA(A) receptors did not reflect global changes in receptor expression, because the magnitude of GABA and glycine responses was similar at P13 in the parent-cell bodies of the calyces, the bushy cells of the cochlear nucleus. In outside-out patches excised from the nonsynaptic face of calyces, GABA and glycine evoked single-channel currents consistent with the properties of postsynaptic GABA(A) and glycine receptors. Inhibitory GABA(B) receptors were present on the calyx at all developmental stages examined. Thus, GABA initially acts on two receptor subtypes, both promoting and inhibiting glutamate release. With age, the former role is transferred to the glycine receptor during the period in which postsynaptic glycinergic transmission is acquired.

Animals↗
PubMed2002

Modulation of transmitter release at giant synapses of the auditory system.

The relay nuclei of the auditory brainstem contain some of the largest nerve terminals in the mammalian brain. Endbulb and calyceal synapses convey signals with a high degree of precision and reliability. However, recent studies reveal that these synapses possess numerous and remarkably diverse mechanisms for the modulation of transmitter release. The implication is that successful relay of signals in vivo may require the ability to fine-tune synaptic transmission.

Animals↗