Receptor saturation controls short-term synaptic plasticity at corticothalamic synapses

Glutamatergic synapses of layer 6 corticothalamic (CT) neurons form a major excitatory input onto thalamic relay cells, allowing neocortex to continuously control sensory information processing in thalamic circuits. CT synapses display both short- and long-term forms of use-dependent synaptic enhancement, mediated at least in part by increases in the probability of transmitter release. At some synapses, such increases in release probability are accompanied by a higher degree of multivesicular release (MVR) and larger glutamate transients at individual release sites, resulting in the saturation of postsynaptic receptors. The extent to which MVR and postsynaptic saturation interact and control short-term plasticity at CT synapses is not known. Here we examined two distinct presynaptic forms of short-term enhancement, facilitation and augmentation, at CT synapses contacting relay neurons in the ventrobasal nucleus of the mouse thalamus. We found that, in the presence of the low-affinity antagonist γ-d-glutamylglycine, to relieve postsynaptic dl-α-amino-3-hydroxy-5-methylisox azole-propionic acid (AMPA) receptor saturation, the magnitude of facilitation and augmentation increased. Whereas receptor saturation was prominent for both AMPA and N-methyl-d-aspartate receptors, desensitization of AMPA receptors did not significantly alter short-term plasticity. Our results suggest that at CT synapses the activity-dependent increase in synaptic strength is controlled by postsynaptic receptor saturation.

Epigastric Antinociception by Cervical Dorsal Column Lesions in Rats

Background Previous clinical evidence and electrophysiologic studies in the authors' laboratory have implicated the dorsal column (DC) as an important pathway for the transmission of visceral colorectal pain. This study examined, behaviorally and electrophysiologically, the role of the DC in mediating epigastric nociception using a visceral pain model involving duodenal distension in rats. Methods For behavioral testing, the writhing-like responses produced in awake rats by graded intraduodenal balloon distension (0.1 to 0.7 ml) were tested. A DC mechanical lesion at the C2 level or a sham operation (SH, same spinal cord segment exposed but no DC lesion) was performed. The writhing-like responses to duodenal distension were tested again and the rats were compared with other rats with no lesions and with SH rats. For electrophysiologic testing, the extracellular activity of single neurons was recorded in the ventrobasal nucleus of the thalamus in anesthetized rats. The ventrobasal cells that responded to duodenal distension were tested further with this visceral stimulus before and after a lesion of the DC. Results The mechanical DC lesion significantly reduced the intensity of the writhing-like responses and increased the threshold volume that would elicit writhing-like responses compared with rats with no lesions and SH rats without any observable neurologic deficit. A lesion of the DC also significantly reduced the responses of ventrobasal cells to duodenal distension. Conclusions The DC plays an important role in signaling epigastric nociception in this experimental model. A mechanical DC lesion can produce significant visceral antinociception in rats.

Facilitation of L-type Calcium Current in Thalamic Neurons

Kammermeier, Paul J. and Stephen W. Jones. Facilitation of L-type calcium current in thalamic neurons. J. Neurophysiol. 79: 410–417, 1998. We have studied facilitation of the L-type calcium current in neurons acutely isolated from the ventrobasal nucleus of the rat thalamus. Currents were recorded after pretreatment with 1 μM ω-conotoxin GVIA and 5 μM ω-conotoxin MVIIC, to better isolate L-current. Long, strong depolarizations induced slow tail currents at negative voltages, but did not affect currents at voltages where channels were strongly activated. The initial peak tail current was not measurably increased. The time course of recovery from facilitation paralleled the time course of the tail current, indicating that facilitation does not outlast channel closing. The kinase inhibitors staurosporine and H-7 and the phosphatase inhibitor okadaic acid had no significant effect on L-current facilitation compared with control, but facilitation was greater with H-7 than with okadaic acid. The guanosine 5′-triphosphate (GTP) analogs GTP-γ-S and GDP-β-S did not affect facilitation. We conclude that L-current facilitation in thalamic neurons does not result from Ser/Thr phosphorylation, although phosphorylation may modulate facilitation. This form of facilitation differs kinetically and pharmacologically from facilitation induced by activation of G protein-coupled receptors.

High-Voltage-Activated Calcium Currents in Neurons Acutely Isolated From the Ventrobasal Nucleus of the Rat Thalamus

Kammermeier, Paul J. and Stephen W. Jones. High-voltage-activated calcium currents in neurons acutely isolated from the ventrobasal nucleus of the rat thalamus. J. Neurophysiol. 77: 465–475, 1997. We studied the high-voltage-activated (HVA) calcium currents in cells isolated from the ventrobasal nucleus of the rat thalamus with the use of the whole cell patch-clamp technique. Low-voltage-activated current was inactivated by the use of long voltage steps or 100-ms prepulses to −20 mV. We used channel blocking agents to characterize the currents that make up the HVA current. The dihydropyridine (DHP) antagonist nimodipine (5 μM) reversibly blocked 33 ± 1% (mean ± SE), and ω-conotoxin GVIA (1 μM) irreversibly blocked 25 ± 5%. The current resistant to DHPs and ω-conotoxin GVIA was inhibited almost completely by ω-conotoxin MVIIC (90 ± 5% at 3–5 μM) and was partially inhibited by ω-agatoxin IVA (54 ± 4% block at 1 μM). We conclude that there are at least four main HVA currents in thalamic neurons: N current, L current, and two ω-conotoxin MVIIC-sensitive currents that differ in their sensitivity to ω-agatoxin IVA. We also examined modulation of HVA currents by strong depolarization and by G protein activation. Long (∼1 s), strong depolarizations elicited large, slowly deactivating tail currents, which were sensitive to DHP antagonists. With guanosine 5′-O-(3-thiotriphosphate) (GTP-γ-S) in the intracellular solution, brief (∼20 ms), strong depolarization produced a voltage-dependent facilitation of the current (44 ± 5%), compared with cells with GTP (22 ± 7%) or guanosine 5′-O-(2-thiodiphosphate) (7 ± 4%). However, the HVA current was inhibited only weakly by 100 μM acetylcholine (8 ± 4%). Effects of the γ-aminobutyric acid-B agonist baclofen were variable (3–39% inhibition, n = 12, at 10–50 μM).