Synapse-glia interactions are governed by synaptic and intrinsic glial properties.

It is believed that glial cell activation and their interactions with synapses are predominantly dependent upon the characteristics of synaptic activity and the level of transmitter release. Because synaptic properties vary from one type of synapse to another, synapse-glia interactions should differ accordingly. The goal of this work was to examine how glial cell activation is dependent upon the properties of their respective synapses as well as the level of synaptic activity. We contrasted Ca(2+) responses of perisynaptic Schwann cells (PSCs) at neuromuscular junctions (NMJs) with different synaptic properties; the slow-twitch soleus (SOL) and the fast-twitch levator auris longus (LAL) muscles. Amplitude of PSC Ca(2+) responses elicited by repeated motor nerve stimulation at 40, 50 and 100 Hz were larger and their kinetics faster at LAL NMJs and this, at all frequencies examined. In addition, a greater number of PSCs per NMJ was activated by sustained synaptic transmission at NMJs of LAL in comparison to SOL. Differences in PSC activation could not be explained solely by differences in levels of transmitter release but also by intrinsic PSC properties since increasing transmitter release with tetraethylammonium chloride (TEA) did not increase their responsiveness. As a whole, these results indicate that PSC responsiveness at NMJs of slow- and fast-twitch muscles differ not only according to the level of activity of their synaptic partner but also in accordance with inherent glial properties.

Synapse-glia interactions at the mammalian neuromuscular junction.

Perisynaptic Schwann cells (PSCs) play critical roles in regulating and stabilizing nerve terminals at the mammalian neuromuscular junction (NMJ). However, although these functions are likely regulated by the synaptic properties, the interactions of PSCs with the synaptic elements are not known. Therefore, our goal was to study the interactions between mammalian PSCs in situ and the presynaptic terminals using changes in intracellular Ca(2+) as an indicator of cell activity. Motor nerve stimulation induced an increase in intracellular Ca(2+) in PSCs, and this increase was greatly reduced when transmitter release was blocked. Furthermore, local application of acetylcholine induced Ca(2+) responses that were blocked by the muscarinic antagonist atropine and mimicked by the muscarinic agonist muscarine. The nicotinic antagonist alpha-bungarotoxin had no effect on Ca(2+) responses induced by acetylcholine. Local application of the cotransmitter ATP induced Ca(2+) responses that were unaffected by the P2 antagonist suramin, whereas local application of adenosine induced Ca(2+) responses that were greatly reduced by the A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT). However, the presence of the A1 antagonist in the perfusate did not block responses induced by ATP. Ca(2+) responses evoked by stimulation of the motor nerve were reduced in the presence of CPT, whereas atropine almost completely abolished them. Ca(2+) responses were further reduced when both antagonists were present simultaneously. Hence, PSCs at the mammalian NMJ respond to the release of neurotransmitter induced by stimulation of the motor nerve through the activation of muscarinic and adenosine A1 receptors.

Behavioral reactivity to aversive stimuli in a transgenic mouse model of impaired glucocorticoid (type II) receptor function: effects of diazepam and FG-7142.

Transgenic mice with impaired type II-glucocorticoid receptor mediated feedback inhibition of hypthalamic-pituitary-adrenal activity were assessed in three different tests assessing behavioral reactivity to aversive stimuli, the elevated plus maze, the Thatcher-Britton novelty-conflict paradigm, and the startle paradigm. Transgenic mice more frequently entered and spent more time in the open arms of the elevated plus in comparison to B6C/3F1 mice. Transgenic mice took significantly longer to begin eating in the Thatcher-Britton novelty conflict paradigm, and displayed increased reactivity in the startle paradigm. Administration of 1 or 2 mg/kg diazepam reversed the behavioral effects observed in all three tests. Administration of the benzodiazepine receptor inverse agonist N-methyl-beta-carboline-3 carboxamide (FG-7142, 10 mg/kg) reduced the ratio of open to total arm entries and the time spent in the open arms of the plus maze in transgenic, but not B6C/3F1, mice. This dose of FG-7142 did not influence performance of either strain in the Thatcher-Britton or startle paradigms. These results are discussed in terms of the hypothesis that the transgenic mice are more sensitive to the aversive properties of novel stimuli, and that they may have difficulty discriminating between signals of relative safety and danger.

Spatial memory in transgenic mice with impaired glucocorticoid receptor function.

Spatial learning and memory function of transgenic mice with impaired glucocorticoid receptor function was assessed in the Morris water maze and the radial arm maze. Transgenic mice took longer to find a submerged and a visual platform in the water maze task than did mice from the parent strain (B6C/3F1), although performance was improved in the visible platform condition relative to the submerged platform task. In the radial arm maze, transgenic mice made significantly more errors than B6C/3F1 mice. In both tasks, the behavioural strategies adopted by transgenic mice were non-optimal for correct performance. It is suggested that the impaired performance displayed by transgenic mice in both tests is largely attributable to these altered behavioural strategies.

The effect of quisqualic acid-induced lesions of the nucleus basalis magnocellularis on latent inhibition.

Latent inhibition (LI) is a reduction in the rate of acquisition of a Pavlovian conditioned response that results from prior nonreinforced preexposure to a conditioned stimulus (CS). LI has been suggested to reflect the operation of mechanisms involved in stimulus selection for subsequent cognitive processing. The present experiment was conducted to assess the effect of bilateral lesions of the nucleus basalis magnocellularis (NBM) on LI employing a conditioned emotional response paradigm. Bilateral lesions of the NBM were produced by administration of 0.12 M quisqualic acid and resulted in decreased cortical acetylcholinesterase staining, as well as a 40% reduction in cortical choline acetyltransferase activity. Following lever press training, preexposed animals received 40 presentations of a 60-s tone CS. Nonpreexposed animals received no tone presentations. Acquisition of conditioned suppression was then assessed over the course of 4 tone-shock (0.6 mA, 0.5 s) pairings. Control, preexposed animals displayed a retarded rate of acquisition in comparison to nonpreexposed controls, thereby demonstrating that the parameters used in the present experiment produced LI. In contrast, lesioned animals preexposed to the CS acquired conditioned suppression as readily as nonpreexposed lesioned animals. However, the acquisition of conditioned suppression in both lesioned groups was found to be similar to that displayed in the preexposed control group. This pattern of results was interpreted as being attributable to a lesion-induced impairment in the ability to maintain stimulus processing, rather than a deficit in the ability to filter a stimulus.

Transplants to the cerebral cortex of nucleus basalis magnocellularis-lesioned rats: effects on deficits in latent inhibition.

Bilateral quisqualic acid-induced lesions of the nucleus basalis magnocellularis (nbm) in rats disrupted the expression of latent inhibition, a phenomenon thought to be dependent upon selective attention processes. Since grafts of adrenal chromaffin cells to the cerebral cortex of nbm-lesioned rats have been shown to ameliorate other lesion-induced cognitive deficits, we tested here whether expression of latent inhibition could be reinstated by graft placement. Interestingly, grafts of either chromaffin cells or cells from kidney or liver that have been used previously as control grafts, were able to restore latent inhibition in lesioned animals. These results suggest that it may be a host response to graft placement rather than a factor supplied by the grafted tissue itself that is responsible for the amelioration of lesion-induced deficits of latent inhibition.