Age-related changes of hippocampal synaptic plasticity in AßPP-null mice are restored by NGF through p75NTR.

Amyloid-ß protein precursor (AßPP) is a ubiquitous protein found in all cell types, suggesting basic and yet important roles, which still remain to be fully elucidated. Loss of function of AßPP has been linked to abnormal neuronal morphology and synaptic function within the hippocampus and alterations in spatial learning, suggesting a neurotrophic role for this protein. Besides AßPP, nerve growth factor (NGF) and other neurotrophins have also been shown to finely modulate neuronal excitability, synaptic plasticity, and cognitive functions. In addition, recent data support the hypothesis of a functional interconnection between AßPP and NGF pathway. Here, we demonstrated that loss of AßPP function, leading to progressive decrease of choline acetyltransferase expression in the septum, correlates with age-related impairment of long-term potentiation (LTP) in the dentate gyrus. We next addressed whether impaired hippocampal plasticity in AßPP-null mice can be restored upon NGF treatment. Notably, NGF, as well as Pro-NGF, can fully revert LTP deficits in AßPP-null mice through p75NTR and JNK pathway activation. Overall the present study may unveil a new mechanism by which, in the absence of AßPP, NGF treatment may preferentially direct p75-neurotrophin-dependent JNK activation toward regeneration and plasticity in functionally relevant brain circuits.

N-ethyl lidocaine (QX-314) protects striatal neurons against ischemia: an in vitro electrophysiological study.

In this study, we have investigated the neuroprotective actions of the membrane impermeable, lidocaine analog, N-ethyl lidocaine (QX-314) in the striatum. The effects of this drug were compared with those caused by the strictly-related-compound and sodium channel blocker lidocaine. To address this issue, electrophysiological recordings were performed in striatal slices, in control condition (normoxia) and during combined oxygen and glucose deprivation (in vitro ischemia). Either QX-314 or lidocaine induced, to some extent, a protection of the permanent electrophysiological alteration (field potential loss) caused by a period (12 min) of ischemia. Thus, both compounds permitted a partial recovery of the ischemic depression of the corticostriatal transmission and reduced the amplitude of the ischemic depolarization in medium spiny neurons. However, while QX-314, at the effective concentration of 100 microM, slightly reduced the amplitude of the excitatory field potential and did not affect the current-evoked spikes discharge of medium spiny striatal neurons, equimolar lidocaine depressed the field potential and eliminated repetitive spikes on a depolarizing step. On the basis of these observations, our results suggest the use of QX-314 as a neuroprotective agent in ischemic brain disorders.

Differential effect of carbamazepine and oxcarbazepine on excitatory synaptic transmission in rat hippocampus.

In this study, we have compared the effects of two structurally related compounds carbamazepine (CBZ) and oxcarbazepine (OXC), both in current use for the treatment of epilepsy and bipolar disorder, on fast excitatory transmission in rat hippocampal slices. Using electrophysiological recordings, we have investigated the effects of CBZ and OXC on repetitive action potential discharge of CA1 pyramidal neurons demonstrating that both compounds produced firing inhibition with similar IC(50) values. Moreover, we show that bath applied CBZ (0.01-1 mM) exerted a concentration-dependent decrease in the amplitude of the field excitatory postsynaptic potentials with an IC(50) of approximately 194.3 microM. When OXC was used at the same concentrations, the concentration-response curve was shifted to the right (IC(50) of approximately 711.07 microM). In addition, we demonstrated that CBZ and OXC reduced, to a different extent, both evoked excitatory postsynaptic currents and NMDA-, AMPA-, and KA-mediated inward currents, CBZ being more potent than OXC. These data highlight distinct presynaptic and postsynaptic sites of action for both compounds and suggest that CBZ, by markedly depressing postsynaptic ionotropic glutamate receptors-mediated responses, may produce more severe cognitive and memory impairment. Thus, we assume that relatively high doses of OXC could be better tolerated than therapeutically equivalent doses of CBZ, justifying the preferential use of OXC as first-line treatment in the therapy of neurological and psychiatric disorders, particularly when compared with CBZ.

The blockade of K(+)-ATP channels has neuroprotective effects in an in vitro model of brain ischemia.

There is a common belief that the opening of K(+)-ATP channels during an ischemic episode has protective effects on neuronal functions by inducing a reduction in energy consumption. However, recent studies have also proposed that activation of these channels might have deleterious effects on cell's survival possibly after a stroke or during long-lasting neurodegenerative processes. Considering these contrasting results, we have used a hippocampal in vitro slice preparation in order to investigate the possible effects of K(+)-ATP channel blockers on the electrophysiological and morphological changes induced by a transient episode of ischemia (oxygen and glucose deprivation) on CA1 pyramidal neurons. Therefore, we found that tolbutamide and glibenclamide, both nonselective K(+)-ATP channel blockers, produce neuroprotective effects against in vitro ischemia. Interestingly, the mitochondrial K(+)-ATP channel blocker 5-hydroxydecanoate and various K(+) channel blockers did not exert neuroprotection. Our results are consistent with the concept that a decreased activity of the plasmalemmal K(+)-ATP conductances may have a protective effect during episodes of transient cerebral ischemia.

Cellular localization of TRPC3 channel in rat brain: preferential distribution to oligodendrocytes.

In the present work we describe the cellular localization of TRPC3 in non-excitable cells as compared to the neurons in normal rat brain. We performed a double labeling study for TRPC3 and one of the following cell-specific markers: mouse anti-glial fibrillary acidic protein (GFAP) for astrocytes; mouse anti-RIP for oligodendrocytes, or mouse anti-OX42 for microglia, or mouse anti-NeUN for neuronal nuclei or mouse anti-tyrosine hydroxylase (TH) for detection of dopaminergic neurons of the substantia nigra. Our double label immunofluorescence study showed that that TRPC3 is mainly localized in oligodendrocytes. These result were confirmed by the electron microscopy study, which showed TRPC3 immunoreactivity in oligodendrocytes. Consistent with the evidence that calcium homeostasis is important to oligodendrocytes for development, myelination, and demyelination [Microsc. Res. Tech. 52 (2001) 672], we can speculate that the distribution of TRPC3 in oligodendrocytes plays a role in myelination and or demyelination processes.

Enhanced anandamide degradation is associated with neuronal apoptosis induced by the HIV-1 coat glycoprotein gp120 in the rat neocortex.

Human immunodeficiency virus type-1 coat glycoprotein gp120 causes delayed apoptosis in rat brain neocortex. Here, we investigated the possible role of the endocannabinoid system in this process. It is shown that gp120 causes a time-dependent increase in the activity and immunoreactivity of the anandamide (AEA)-hydrolyzing enzyme fatty acid amide hydrolase (FAAH), paralleled by increased activity of the AEA membrane transporter and decreased endogenous levels of AEA. The AEA-synthesizing phospholipase D and the AEA-binding receptors were not affected by gp120. None of the changes induced by gp120 in the cortex were induced by bovine serum albumin, nor were they observed in the hippocampus of the same animals. Also, the activity of 5-lipoxygenase, which generates AEA derivatives able to inhibit FAAH, decreased down to approximately 25% of the control activity upon gp120 treatment, due to reduced protein level ( approximately 45%). In addition, the FAAH inhibitor methyl-arachidonoyl fluorophosphonate significantly reduced gp120-induced apoptosis in rat brain neocortex, whereas selective blockers of AEA membrane transporter or of AEA-binding receptors were ineffective. Taken together, these results suggest that gp120, by activating FAAH, decreases endogenous levels of AEA, and the latter effect seems instrumental in the execution of delayed neuronal apoptosis in the brain neocortex of rats.

Involvement of a glutamergic mechanism in gamma-dendrotoxin-induced hippocampal neuronal cell loss in the rat.

The epileptogenic and neurodegenerative effects of gamma-dendrotoxin, from Dendroaspis angusticeps, a specific blocker of a non-inactivating, voltage-sensitive K+ channel, were studied after focal injection into one dorsal hippocampus in rats pretreated with CGP040116, a N-methyl-D-aspartate (NMDA) receptor antagonist, and in rats bearing a monolateral surgical lesion of the Schaffer collaterals whose terminals originate from CA3 pyramids and release glutamate in the CA1 hippocampal area. Administration of 35 pmol gamma-dendrotoxin elicited in all of the treated animals (n=8) bilateral EEG discharges and damage to the hippocampal formation. Quantitation of the damage revealed significant bilateral neuronal cell loss in the CA1, CA3 and CA4 pyramidal cell layers. The lowest dose (0.35 pmol; n=4) of the toxin used did not affect EEG activity and failed to cause significant hippocampal cell loss whereas the 3.5 pmol (n=6) dose caused EEG seizures and hippocampal cell loss limited to the CA1 area. Systematic intraperitoneal administration of CGP040116 (5mg/kg given 30 min. previously) delayed the onset of EEG seizures and reduced the number of epileptogenic discharges typically observed in rats receiving an injection of gamma-dendrotoxin (35 pmol) alone. Similarly, this treatment prevented the damage inflicted to the hippocampus by the toxin and in no instance was significant neuronal loss observed. Protection against seizures and hippocampal damage was also observed by a monolateral surgical lesion to the Schaffer collaterals. In conclusion, the present data suggest that an excitotoxic, glutamate-mediated, type of mechanism underlies seizures and hippocampal damage induced by gamma-dendrotoxin in rats.