Early cognitive deficit characteristic of early Alzheimer's disease seems to be produced by the soluble forms of beta-amyloid protein. Such cognitive deficit correlates with neuronal network dysfunction that is reflected as alterations in the electroencephalogram of both Alzheimer patients and transgenic murine models of such disease. Correspondingly, recent studies have demonstrated that chronic exposure to betaAP affects hippocampal oscillatory properties. However, it is still unclear if such neuronal network dysfunction results from a direct action of betaAP on the hippocampal circuit or it is secondary to the chronic presence of the protein in the brain. Therefore, we aimed to explore the effect of acute exposure to betaAP(25-35) on hippocampal network activity both in vitro and in vivo, as well as on intrinsic and synaptic properties of hippocampal neurons. We found that betaAP(25-35), reversibly, affects spontaneous hippocampal population activity in vitro. Such effect is not produced by the inverse sequence betaAP(35-25) and is reproduced by the full-length peptide betaAP(1-42). Correspondingly betaAP(25-35), but not the inverse sequence betaAP(35-25), reduces theta-like activity recorded from the hippocampus in vivo. The betaAP(25-35)-induced disruption in hippocampal network activity correlates with a reduction in spontaneous neuronal activity and synaptic transmission, as well as with an inhibition in the subthreshold oscillations produced by pyramidal neurons in vitro. Finally, we studied the involvement of Fyn-kinase on the betaAP(25-35)-induced disruption in hippocampal network activity in vitro. Interestingly, we found that such phenomenon is not observed in slices obtained from Fyn-knockout mice. In conclusion, our data suggest that betaAP acutely affects proper hippocampal function through a Fyn-dependent mechanism. We propose that such alteration might be related to the cognitive impairment observed, at least, during the early phases of Alzheimer's disease.

Water gain in the brain consequent to hyponatremia is counteracted by mechanisms that initially include a compensatory displacement of liquid from the interstitial space to cerebrospinal fluid and systemic circulation and subsequently an active reduction in cell water accomplished by extrusion of intracellular osmolytes to reach osmotic equilibrium. Potassium (K+), chloride (Cl-), amino acids, polyalcohols, and methylamines all contribute to volume regulation, with a major contribution of ions at the early phase and of organic osmolytes at the late phase of the regulatory process. Experimental models in vitro show that osmolyte fluxes occur via leak pathways for organic osmolytes and separate channels for Cl- and K+. Osmotransduction signaling cascades for Cl- and taurine efflux pathways involve tyrosine kinases and phosphoinositide kinases, while Ca2+ and serine-threonine kinases modulate K+ pathways. In-depth knowledge of the cellular and molecular adaptive mechanisms of brain cells during hyponatremia contributes to a better understanding of the associated complications, including the risks of inappropriate correction of the hyponatremic condition.

Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine-treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation.

TRPC5 forms Ca2؉ -permeable nonselective cation channels important for neurite outgrowth and growth cone morphology of hippocampal neurons. Here we studied the activation of mouse TRPC5 expressed in Chinese hamster ovary and human embryonic kidney 293 cells by agonist stimulation of several receptors that couple to the phosphoinositide signaling cascade and the role of calmodulin (CaM) on the activation. We showed that exogenous application of 10 M CaM through patch pipette accelerated the agonist-induced channel activation by 2.8-fold, with the time constant for half-activation reduced from 4.25 ؎ 0.4 to 1.56 ؎ 0.85 min. We identified a novel CaM-binding site located at the C terminus of TRPC5, 95 amino acids downstream from the previously determined common CaM/IP 3 Rbinding (CIRB) domain for all TRPC proteins. Deletion of the novel CaM-binding site attenuated the acceleration in channel activation induced by CaM. However, disruption of the CIRB domain from TRPC5 rendered the channel irresponsive to agonist stimulation without affecting the cell surface expression of the channel protein. Furthermore, we showed that high (>5 M) intracellular free Ca 2؉ inhibited the current density without affecting the time course of TRPC5 activation by receptor agonists. These results demonstrated that intracellular Ca 2؉ has dual and opposite effects on the activation of TRPC5. The novel CaM-binding site is important for the Ca 2؉ /CaM-mediated facilitation, whereas the CIRB domain is critical for the overall response of receptor-induced TRPC5 channel activation.In 1994, we demonstrated (1, 2) that the transient receptor potential (Trp) 1 gene and its homologue, Trp-like (Trpl), fromDrosophila melanogaster encoded calcium-permeable cationic channels activated either by store depletion or by stimulation of G q/11 -coupled receptors. These initial findings prompted the search for mammalian homologues, leading to the identification of seven TRP genes with different degrees of sequence similarity to the original insect Trp gene (3). These genes are now designated TRP-Canonical or TRPC, symbolizing their close similarity to the original Drosophila Trp. Many recently discovered cation channels are found to share some limited homology with the TRPCs. These include TRPVs (similar to the vanilloid receptor), TRPMs (named after the first identified member, melastatin), and TRPPs (named after PKD2 for polycystic kidney disease), etc. Together, there are at least 28 non-allelic TRP genes in the mammalian genome. The TRP channels serve diverse functions in many tissues from somatosensory to cardiovascular systems (4). TRPC5 is a member of the TRPC family of Ca 2ϩ -permeable nonselective cationic channels. It has drawn attention recently because of its role in modulating hippocampal growth cone motility and neurite elongation in the mammalian brain (5). The TRPC5 channel activity is induced upon stimulation of the phosphoinositide signaling cascade by receptors that stimulate phospholipase C; however, the exact mechanism of channel activ...