HIV- and FIV-derived gp120 alter spatial memory, LTP, and sleep in rats.

Human immunodeficiency virus (HIV)-associated dementia (HAD) has been detected in 20-30% of patients suffering AIDS. The envelope glycoprotein 120 (gp120) derived from HIV seems to play a critical role in the pathophysiology of this dementia. Likewise, the feline immunodeficiency virus (FIV)-derived gp120 causes neurological and electrophysiological abnormalitites in cats. We have studied the effects of gp120 derived from HIV or FIV on learning and memory processing, hippocampal long-term potentiation (LTP), hippocampal neuronal cAMP production, the sleep-waking cycle, and locomotor activity and equilibrium in rats. Results showed that while both HIV- and FIV-gp120 impaired the rat's performance in the Barnes maze task, only HIVgp120 impaired the induction and maintenance of LTP. However, both glycoproteins induced a significant decrease in the posttetanic potentiation. HIVgp120 also caused a significant reduction in cAMP production in the hippocampus. Regarding the sleep-waking cycle, HIV- and FIV-gp120 increased the waking state and slow-wave sleep 1 (SWS1), while decreasing both SWS2 and REM sleep. Locomotor activity and equilibrium were significantly altered by these glycoproteins. These results suggest that HIVgp120 causes neurophysiological abnormalities and therefore may facilitate HAD development in AIDS patients.

Cortistatin modulates memory processes in rats.

Cortistatin (CST) is a recently described neuropeptide with high structural homology with somatostatin. Its mRNA is restricted to gamma amino butyric acid (GABA)-containing cells in the cerebral cortex and hippocampus. CST modulates the electrophysiology of the hippocampus and cerebral cortex of rats; hence, it may be modulating mnemonic processes. In this study, we have evaluated the effect of CST and somatostatin (SS) on short- and long-term memory (STM and LTM, respectively), as well as on the extinction of the behavior by using the footshock passive avoidance behavioral test. In addition, we tested the ability of both neuropeptides to affect the generation of cAMP in hippocampal neurons in culture. Results showed that the administration of either CST or SS into the hippocampal CA1 deteriorates memory consolidation in a dose-response fashion and facilitates the extinction of the learned behavior. CST was more potent than SS. Likewise, CST increases cAMP while SS decreases it. These results strongly support a modulatory role for CST in memory processes.

Properties of the ryanodine-sensitive release channels that underlie caffeine-induced Ca2+ mobilization from intracellular stores in mammalian sympathetic neurons.

The most compelling evidence for a functional role of caffeine-sensitive intracellular Ca2+ reservoirs in nerve cells derives from experiments on peripheral neurons. However, the properties of their ryanodine receptor calcium release channels have not been studied. This work combines single-cell fura-2 microfluorometry, [3H]ryanodine binding and recording of Ca2+ release channels to examine calcium release from these intracellular stores in rat sympathetic neurons from the superior cervical ganglion. Intracellular Ca2+ measurements showed that these cells possess caffeine-sensitive intracellular Ca2+ stores capable of releasing the equivalent of 40% of the calcium that enters through voltage-gated calcium channels. The efficiency of caffeine in releasing Ca2+ showed a complex dependence on [Ca2+]i. Transient elevations of [Ca2+]i by 50-500 nM were facilitatory, but they became less facilitatory or depressing when [Ca2+]i reached higher levels. The caffeine-induced Ca2+ release and its dependence on [Ca2+]i was further examined by [3H]ryanodine binding to ganglionic microsomal membranes. These membranes showed a high-affinity binding site for ryanodine with a dissociation constant (KD = 10 nM) similar to that previously reported for brain microsomes. However, the density of [3H]ryanodine binding sites (Bmax = 2.06 pmol/mg protein) was at least three-fold larger than the highest reported for brain tissue. [3H]Ryanodine binding showed a sigmoidal dependence on [Ca2+] in the range 0.1-10 microM that was further increased by caffeine. Caffeine-dependent enhancement of [3H]ryanodine binding increased and then decreased as [Ca2+] rose, with an optimum at [Ca2+] between 100 and 500 nM and a 50% decrease between 1 and 10 microM. At 100 microM [Ca2+], caffeine and ATP enhanced [3H]ryanodine binding by 35 and 170% respectively, while binding was reduced by > 90% with ruthenium red and MgCl2. High-conductance (240 pS) Ca2+ release channels present in ganglionic microsomal membranes were incorporated into planar phospholipid bilayers. These channels were activated by caffeine and by micromolar concentrations of Ca2+ from the cytosolic side, and were blocked by Mg2+ and ruthenium red. Ryanodine (2 microM) slowed channel gating and elicited a long-lasting subconductance state while 10 mM ryanodine closed the channel with infrequent opening to the subconductance level. These results show that the properties of the ryanodine receptor/Ca2+ release channels present in mammalian peripheral neurons can account for the properties of caffeine-induced Ca2+ release. Our data also suggest that the release of Ca2+ by caffeine has a bell-shaped dependence on Ca2+ in the physiological range of cytoplasmic [Ca2+].

Properties of the sodium current in rat chromaffin cells exposed to nerve growth factor in vitro.

1. This paper examines the electrophysiological properties of cultured rat adrenal chromaffin cells at different stages of neuron-like morphological differentiation in response to nerve growth factor (NGF). 2. Chromaffin cells display a large variability in the morphological changes after exposure to NGF. However, a marked tendency to neuronal phenotypic transformation prevails after two weeks in culture. 3. The voltage dependence of the macroscopic Na currents, judged by the current to voltage relationship, did not change significantly as a result of NGF treatment. Moreover, when kinetics, half-activation, and half-inactivation parameters of Na currents were compared between control and NGF-treated cells, no significant differences were observed. 4. Peak Na currents in control cells remained < 1 nA throughout the 17 d of observation, whereas currents > 1 nA became more frequent after the first week of NGF exposure. Cells with Na currents > 2 nA were found routinely in cultures exposed to NGF for > or = 15 d, but inadequate voltage control and neurite spiking prevented a thorough examination. Sodium current density in the population of NGF-treated chromaffin cells increased progressively over time, until an apparent plateau (3.5-fold increase) was reached by the end of the second week. No significant changes were observed in control, untreated cells. 5. The increase in Na channel density induced by NGF in chromaffin cells in compatible with the acquisition of the neuronal phenotype. Interestingly, the increase in Na channel expression occurs in slower time scale than in their neoplastic correlate, the PC12 cells. Na channels newly expressed by chromaffin cells after NGF treatment are functionally indistinguishable from those already present before treatment.