Search

Dietary and metabolic therapies are increasingly being considered for a variety of neurological disorders, based in part on growing evidence for the neuroprotective properties of the ketogenic diet (KD) and ketones. Earlier, we demonstrated that ketones afford hippocampal synaptic protection against exogenous oxidative stress, but the mechanisms underlying these actions remain unclear. Recent studies have shown that ketones may modulate neuronal firing through interactions with ATP-sensitive potassium (KATP) channels. Here, we used a combination of electrophysiological, pharmacological, and biochemical assays to determine whether hippocampal synaptic protection by ketones is a consequence of KATP channel activation. Ketones dose-dependently reversed oxidative impairment of hippocampal synaptic integrity, neuronal viability, and bioenergetic capacity, and this action was mirrored by the KATP channel activator diazoxide. Inhibition of KATP channels reversed ketone-evoked hippocampal protection, and genetic ablation of the inwardly rectifying K+ channel subunit Kir6.2, a critical component of KATP channels, partially negated the synaptic protection afforded by ketones. This partial protection was completely reversed by co-application of the KATP blocker, 5-hydoxydecanoate (5HD). We conclude that, under conditions of oxidative injury, ketones induce synaptic protection in part through activation of KATP channels.

Institutions across the country continue to ponder and evaluate strategies for aligning financial aid to complement their enrollment goals. Two Indiana University enrollment managers examine the purposeful application of institutional aid in financial aid packaging. In response to the debate about the of merit-based aid vs. the appropriate share of need-based funding to students, IU is proposing the concept of "cross over" institutional aid in order to meet the relatively new focus on affordability. (Contains 3 tables and 4 figures.)

In state houses around the country, one of the common higher education themes is affordability. As tuition costs have increased at rates exceeding that of inflation, students and families have pressed their legislative representatives to examine these increases. Affordability is a term used by various constituent groups, and its definition varies widely according to the context in which the term is applied. In the broadest sense, affordability is the perception that a product is worth its price. That perception can translate into one student's willingness to pay and another student's ability to pay. A scholarship may offer sufficient incentive to a "no-need" student who now sees greater "worth" in attending a particular school that has already met his academic and personal expectations. A grant may remove the last remaining financial barrier for an academically qualified yet "high-need" student who has never dreamed that he might be able to fulfill his aspirations for a better life. One key to the affordability quotient is the numbers of "crossover" students who enroll (i.e., those who are scholarship eligible and who also have significant need), thus qualifying for scholarships as well as grants. The purpose of this paper is to describe the strategy we used to reach our enrollment goals of increasing access of high-need Hoosiers to Indiana's flagship campus and enhancing the diversity of our freshman resident students. (Contains 5 figures.)

Repeated seizures result in a persistent maladaptation of endocannabinoid (eCB) signaling, mediated part by anandamide signaling deficiency in the basolateral amygdala (BLA) that manifests as aberrant synaptic function and altered emotional behavior. Here, we determined the effect of repeated seizures (kindling) on 2-arachidonoylglycerol (2-AG) signaling on GABA transmission by directly measuring tonic and phasic eCB-mediated retrograde signaling in an in vitro BLA slice preparation from male rats. We report that both activity-dependent and muscarinic acetylcholine receptor (mAChR)-mediated depression of GABA synaptic transmission was reduced following repeated seizure activity. These effects were recapitulated in sham rats by preincubating slices with the 2-AG synthesizing enzyme inhibitor DO34. Conversely, preincubating slices with the 2-AG degrading enzyme inhibitor KML29 rescued activity-dependent 2-AG signaling, but not mAChR-mediated synaptic depression, over GABA transmission in kindled rats. These effects were not attributable to a change in cannabinoid type 1 (CB1) receptor sensitivity or altered 2-AG tonic signaling since the application of the highly selective CB1 receptor agonist CP55,940 provoked a similar reduction in GABA synaptic activity in both sham and kindled rats, while no effect of either DO34 or of the CB1 inverse agonist AM251 was observed on frequency and amplitude of spontaneous IPSCs in either sham or kindled rats. Collectively, these data provide evidence that repeated amygdala seizures persistently alter phasic 2-AG-mediated retrograde signaling at BLA GABAergic synapses, probably by impairing stimulus-dependent 2-AG synthesis/release, which contributes to the enduring aberrant synaptic plasticity associated with seizure activity. [ABSTRACT FROM AUTHOR]

Inflammatory bowel diseases (IBDs) are chronic relapsing and remitting conditions associated with long-term gut dysfunction resulting from alterations to the enteric nervous system and a loss of enteric neurons (1), [...]

To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.tins.2009.11.007 Byline: Brian A. MacVicar (1), Roger J. Thompson (2) Abstract: Pannexins are large-pore ion channels with broad expression in the central nervous system (CNS). The channels function by releasing large signaling molecules, such ATP and arachidonic acid derivatives, from neurons and possibly astrocytes. They might also contribute to novel forms of non-synaptic communication in the CNS, thereby affecting synaptic function, astrocytic Ca.sup.2+ wave propagation and possibly regulation of vascular tone in the brain. Panx1 activation in various in vitro pathological conditions implicates these channels in ischemic, excitotoxic and ATP-dependent cell death, whereas Panx coupling with purinergic receptors triggers the inflammasome. Novel functions for the pannexin channels are likely to be discovered as current understanding of how they are regulated in physiological and pathological situations improves. Author Affiliation: (1) Brain Research Centre, Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada, V6K 1L1 (2) Brimacombe Laboratory for Stroke Research, Hotchkiss Brain Institute, Department of Cell Biology and Anatomy, University of Calgary, Calgary, AB, Canada, T2N 4N1

Anion channels provide a pathway for C[l.sup.-] influx into the lumen of the Golgi cisternae. This influx permits luminal acidification by the organelle's [H.sup.+]-ATPase. Three different experimental approaches, electrophysiological, biochemical, and proteomic, demonstrated that two Golgi anion channels, GOLAC-1 and GOLAC-2, also mediate ATP anion transport into the Golgi lumen. First, GOLAC-1 and -2 were incorporated into planar lipid bilayers, and single-channel recordings were obtained. Low ionic activities of [K.sub.2]ATP added to the cis-chamber directly inhibited the C[l.sup.-] subconductance levels of both channels, with [K.sub.m] values ranging from 16 to 115 [micro]M. Substitution of either [K.sub.2]ATP or MgATP for C[l.sup.-] on the cis, trans, or both sides indicated that ATP is conducted by the channels with a relative permeability sequence of C[l.sup.-] > AT[P.sup.4-] > MgAT[P.sup.2-] Single-channel currents were observed at physiological concentrations of C[l.sup.-] and ATP, providing evidence for their importance in vivo. Second, transport of [[alpha]-[sup.32P]]ATP into sealed Golgi vesicles that maintain in situ orientation was consistent with movement through the GOLACs because it exhibited little temperature dependence and was saturated with an apparent [K.sub.m] = 25 [micro]M. Finally, after transport of [[gamma]-[sup.32P]]ATP, a protease-protection assay demonstrated that proteins are phosphorylated within the Golgi lumen, and after SDS-PAGE, the proteins in the phosphorylated bands were identified by mass spectrometry. GOLAC conductances, [[alpha]-[sup.3P]]]ATP transport, and protein phosphorylation have identical pharmacological profiles. We conclude that the GOLACs play dual roles in the Golgi complex, providing pathways for C[l.sup.-] and ATP influx into the Golgi lumen. Golgi complex; Cl channel; mass spectrometry; phosphorylation