Role of the Astrocytic Na(+), K(+)-ATPase in K(+) Homeostasis in Brain: K(+) Uptake, Signaling Pathways and Substrate Utilization.

This paper describes the roles of the astrocytic Na(+), K(+)-ATPase for K(+) homeostasis in brain. After neuronal excitation it alone mediates initial cellular re-accumulation of moderately increased extracellular K(+). At higher K(+) concentrations it is assisted by the Na(+), K(+), 2Cl(-) transporter NKCC1, which is Na(+), K(+)-ATPase-dependent, since it is driven by Na(+), K(+)-ATPase-created ion gradients. Besides stimulation by high K(+), NKCC1 is activated by extracellular hypertonicity. Intense excitation is followed by extracellular K(+) undershoot which is decreased by furosemide, an NKCC1 inhibitor. The powerful astrocytic Na(+), K(+)-ATPase accumulates excess extracellular K(+), since it is stimulated by above-normal extracellular K(+) concentrations. Subsequently K(+) is released via Kir4.1 channels (with no concomitant Na(+) transport) for re-uptake by the neuronal Na(+), K(+)-ATPase which is in-sensitive to increased extracellular K(+), but stimulated by intracellular Na(+) increase. Operation of the astrocytic Na(+), K(+)-ATPase depends upon Na(+), K(+)-ATPase/ouabain-mediated signaling and K(+)-stimulated glycogenolysis, needed in these non-excitable cells for passive uptake of extracellular Na(+), co-stimulating the intracellular Na(+)-sensitive site. A gradual, spatially dispersed release of astrocytically accumulated K(+) will therefore not re-activate the astrocytic Na(+), K(+)-ATPase. The extracellular K(+) undershoot is probably due to extracellular hypertonicity, created by a 3:2 ratio between Na(+), K(+)-ATPase-mediated Na(+) efflux and K(+) influx and subsequent NKCC1-mediated volume regulation. The astrocytic Na(+), K(+)-ATPase is also stimulated by ß1-adrenergic signaling, which further stimulates hypertonicity-activation of NKCC1. Brain ischemia leads to massive extracellular K(+) increase and Ca(2+) decrease. A requirement of Na(+), K(+)-ATPase signaling for extracellular Ca(2+) makes K(+) uptake (and brain edema) selectively dependent upon ß1-adrenergic signaling and inhibitable by its antagonists.

Role of Glycogenolysis in Memory and Learning: Regulation by Noradrenaline, Serotonin and ATP.

This paper reviews the role played by glycogen breakdown (glycogenolysis) and glycogen re-synthesis in memory processing in two different chick brain regions, (1) the hippocampus and (2) the avian equivalent of the mammalian cortex, the intermediate medial mesopallium (IMM). Memory processing is regulated by the neuromodulators noradrenaline and serotonin soon after training glycogen breakdown and re-synthesis. In day-old domestic chicks, memory formation is dependent on the breakdown of glycogen (glycogenolysis) at three specific times during the first 60 min after learning (around 2.5, 30, and 55 min). The chicks learn to discriminate in a single trial between beads of two colors and tastes. Inhibition of glycogen breakdown by the inhibitor of glycogen phosphorylase 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) given at specific times prior to the formation of long-term memory prevents memory forming. Noradrenergic stimulation of cultured chicken astrocytes by a selective ß2-adrenergic (AR) agonist reduces glycogen levels and we believe that in vivo this triggers memory consolidation at the second stage of glycogenolysis. Serotonin acting at 5-HT2B receptors acts on the first stage, but not on the second. We have shown that noradrenaline, acting via post-synaptic α2-ARs, is also responsible for the synthesis of glycogen and our experiments suggest that there is a readily accessible labile pool of glycogen in astrocytes which is depleted within 10 min if glycogen synthesis is inhibited. Endogenous ATP promotion of memory consolidation at 2.5 and 30 min is also dependent on glycogen breakdown. ATP acts at P2Y1 receptors and the action of thrombin suggests that it causes the release of internal calcium ([Ca(2+)]i) in astrocytes. Glutamate and GABA, the primary neurotransmitters in the brain, cannot be synthesized in neurons de novo and neurons rely on astrocytic glutamate synthesis, requiring glycogenolysis.

Antagonists of the Vasopressin V1 Receptor and of the ß(1)-Adrenoceptor Inhibit Cytotoxic Brain Edema in Stroke by Effects on Astrocytes - but the Mechanisms Differ.

Brain edema is a serious complication in ischemic stroke because even relatively small changes in brain volume can compromise cerebral blood flow or result in compression of vital brain structures on account of the fixed volume of the rigid skull. Literature data indicate that administration of either antagonists of the V1 vasopressin (AVP) receptor or the ß1-adrenergic receptor are able to reduce edema or infarct size when administered after the onset of ischemia, a key advantage for possible clinical use. The present review discusses possible mechanisms, focusing on the role of NKCC1, an astrocytic cotransporter of Na(+), K(+), 2Cl(-) and water and its activation by highly increased extracellular K(+) concentrations in the development of cytotoxic cell swelling. However, it also mentions that due to a 3/2 ratio between Na(+) release and K(+) uptake by the Na(+),K(+)-ATPase driving NKCC1 brain extracellular fluid can become hypertonic, which may facilitate water entry across the blood-brain barrier, essential for development of edema. It shows that brain edema does not develop until during reperfusion, which can be explained by lack of metabolic energy during ischemia. V1 antagonists are likely to protect against cytotoxic edema formation by inhibiting AVP enhancement of NKCC1-mediated uptake of ions and water, whereas ß1-adrenergic antagonists prevent edema formation because ß1-adrenergic stimulation alone is responsible for stimulation of the Na(+),K(+)-ATPase driving NKCC1, first and foremost due to decrease in extracellular Ca(2+) concentration. Inhibition of NKCC1 also has adverse effects, e.g. on memory and the treatment should probably be of shortest possible duration.

Fluxes of lactate into, from, and among gap junction-coupled astrocytes and their interaction with noradrenaline.

Lactate is a versatile metabolite with important roles in modulation of brain glucose utilization rate (CMRglc), diagnosis of brain-injured patients, redox- and receptor-mediated signaling, memory, and alteration of gene transcription. Neurons and astrocytes release and accumulate lactate using equilibrative monocarboxylate transporters that carry out net transmembrane transport of lactate only until intra- and extracellular levels reach equilibrium. Astrocytes have much faster lactate uptake than neurons and shuttle more lactate among gap junction-coupled astrocytes than to nearby neurons. Lactate diffusion within syncytia can provide precursors for oxidative metabolism and glutamate synthesis and facilitate its release from endfeet to perivascular space to stimulate blood flow. Lactate efflux from brain during activation underlies the large underestimation of CMRglc with labeled glucose and fall in CMRO2/CMRglc ratio. Receptor-mediated effects of lactate on locus coeruleus neurons include noradrenaline release in cerebral cortex and c-AMP-mediated stimulation of astrocytic gap junctional coupling, thereby enhancing its dispersal and release from brain. Lactate transport is essential for its multifunctional roles.

Serotonin mediation of early memory formation via 5-HT2B receptor-induced glycogenolysis in the day-old chick.

Investigation of the effects of serotonin on memory formation in the chick revealed an action on at least two 5-HT receptors. Serotonin injected intracerebrally produced a biphasic effect on memory consolidation with enhancement at low doses and inhibition at higher doses. The non-selective 5-HT receptor antagonist methiothepin and the selective 5-HT2B/C receptor antagonist SB221284 both inhibited memory, suggesting actions of serotonin on at least two different receptor subtypes. The 5-HT2B/C and astrocyte-specific 5-HT receptor agonist, fluoxetine and paroxetine, enhanced memory and the effect was attributed to glycogenolysis. Inhibition of glycogenolysis with a low dose of DAB (1,4-dideoxy-1,4-imino-D-arabinitol) prevented both serotonin and fluoxetine from enhancing memory during short-term memory but not during intermediate memory. The role of serotonin on the 5-HT2B/C receptor appears to involve glycogen breakdown in astrocytes during short-term memory, whereas other published evidence attributes the second period of glycogenolysis to noradrenaline.

Rapid turnover of glycogen in memory formation.

The influence of noradrenaline acting at α(2)-AR and ß(2)-ARs on the turnover of glycogen after learning has been investigated. The role of glycogen turnover in memory formation was examined using weakly-reinforced, single trial bead discrimination training in day-old domestic chickens. This study follows our previous work that focused on the need for glycogen breakdown (glycogenolysis) during learning. Inhibition of glycogenolysis by 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) prevented the consolidation of strongly-reinforced learning and inhibited memory. The action of DAB could be prevented by stimulating glycogenolysis with the selective ß(2)-AR agonist, zinterol. Stimulation of α(2)-ARs has been shown to lead to an increase in the turnover and synthesis of glycogen. In the present study, we examined the effect of inhibition of α(2)-AR stimulated glycogen turnover (measured as(14)C-glucose incorporation into glycogen) on the ability of zinterol to promote the consolidation of weakly reinforced memory. In astrocytes, the selective α(2)-AR agonist clonidine stimulated (14)C-glucose incorporation into glycogen in chick astrocytes and this was inhibited by the selective α(2)-AR antagonist, ARC239. The critical importance of the timing of ARC239 injection relative to training and intracerebral administration of zinterol was examined. It is concluded that our data provides evidence for a readily accessible labile pool of glycogen in brain astrocytes. If glycogen synthesis is inhibited, the can be depleted within 10 min, thus preventing zinterol from promoting consolidation.

Role for purinergic receptors in memory processing in young chicks.

The current study used a single trial bead discrimination task for the young chick to ascertain if inhibitors of P2 purinergic receptors would impair memory retention. Suramin and PPADS provided similar retention profiles. Loss of memory retention was evident by 60 min post-training. Both drugs caused persistent memory loss which was still evident 24h post-training. These findings suggest that P2 receptors have a role in memory processing.

α2-Adrenoceptors activate noradrenaline-mediated glycogen turnover in chick astrocytes.

In the brain, glycogen is primarily stored in astrocytes where it is regulated by several hormones/neurotransmitters, including noradrenaline that controls glycogen breakdown (in the short term) and synthesis. Here, we have examined the adrenoceptor (AR) subtype that mediates the glycogenic effect of noradrenaline in chick primary astrocytes by the measurement of glycogen turnover (total (14) C incorporation of glucose into glycogen) following noradrenergic activation. Noradrenaline and insulin increased glycogen turnover in a concentration-dependent manner. The effect of noradrenaline was mimicked by stimulation of α(2) -ARs (and to a lesser degree by ß(3) -ARs), but not by stimulation of α(1) -, ß(1) -, or ß(2) -ARs, and occurred only in astrocytes and not neurons. In chick astrocytes, studies using RT-PCR and radioligand binding showed that α(2A) - and α(2C) -AR mRNA and protein were present. α(2) -AR- or insulin-mediated glycogen turnover was inhibited by phosphatidylinositol-3 kinase inhibitors, and both insulin and clonidine caused phosphorylation of Akt and glycogen synthase kinase-3 in chick astrocytes. α(2) -AR but not insulin-mediated glycogen turnover was inhibited by pertussis toxin pre-treatment indicating involvement of Gi/o proteins. These results show that the increase in glycogen turnover caused by noradrenaline is because of activation of α(2) -ARs that increase glycogen turnover in astrocytes utilizing a Gi/o-PI3K pathway.

ATP derived from astrocytes modulates memory in the chick.

Memory consolidation in a discriminative bead pecking task is modulated by endogenous adenosine triphosphate (ATP) acting at purinergic receptors in the hippocampus. Consolidation, from short- to intermediate- to long-term memory during two distinct periods following training, was blocked by the non-selective P2 purinergic receptor antagonist PPADS (pyridoxal phosphate-6-azo(benzene-2,4-disulphonic acid) tetrasodium salt hydrate and the specific P2Y1 receptor antagonist MRS2179. Direct injections of the ATP agonists (ATPγS and ADPßS) potentiated memory consolidation and the effect of ADPßS was blocked by MRS2179, suggesting an important role of ATP on memory consolidation via the P2Y1 receptor in the chick hippocampus. Incubation of astrocytes with ATPγS and ADPßS resulted in the increase of intracellular calcium ([Ca2+]i), the latter being blocked by MRS2179 suggesting a specific role for P2Y1 receptors in the calcium response. This response was prevented by blocking astrocytic oxidative metabolism with fluoroacetate. We argue that the source of the ATP acting on neuronal P2Y1 receptors is most likely to be astrocytes. Thrombin selectively increases [Ca2+]i in astrocytes but not in neurones. The main findings of the present study are: (a) astrocytic [Ca2+]i plays an important role in the consolidation of short-term to long-term memory; and (b) ATP released from chick astrocytes during learning modulates neuronal activity through astrocytic P2Y1 receptors.

Role of ß-adrenoceptors in glucose uptake in astrocytes using ß-adrenoceptor knockout mice.

BACKGROUND AND PURPOSE: ß(1) -, ß(2) - and ß(3) -adrenoceptors determined by functional, binding and reverse transcription polymerase chain reaction (RT-PCR) studies are present in chick astrocytes and activation of ß(2) - or ß(3) -adrenoceptors increase glucose uptake. The aims of the present study are to identify which ß-adrenoceptor subtypes are present in mouse astrocytes, the signal transduction mechanisms involved and whether ß-adrenoceptor stimulation regulates glucose uptake. EXPERIMENTAL APPROACH: Astrocytes were prepared from four mouse strains: FVB/N, DBA/1 crossed with C57BL/6J, ß(3) -adrenoceptor knockout and ß(1) ß(2) -adrenoceptor knockout mice. RT-PCR and radioligand binding studies were used to determine ß-adrenoceptor expression. Glucose uptake and cAMP were assayed to elucidate the signalling pathways involved. KEY RESULTS: mRNAs for all three ß-adrenoceptors were identified in astrocytes from wild-type mice. Radioligand binding studies identified that ß(1) - and ß(3) -adrenoceptors were predominant. cAMP studies showed that ß(1) - and ß(2) -adrenoceptors coupled to G(s) whereas ß(3) -adrenoceptors coupled to both G(s) and G(i) . However, activation of any of the three ß-adrenoceptors increased glucose uptake in mouse astrocytes. Interestingly, there was no functional compensation for receptor subtype loss in knockout animals. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that although ß(1) -adrenoceptors are the predominant ß-adrenoceptor in mouse astrocytes and are primarily responsible for cAMP production in response to ß-adrenoceptor stimulation, ß(3) -adrenoceptors are also present in mouse astrocytes and activation of ß(2) - and ß(3) -adrenoceptors increases glucose uptake in mouse astrocytes.

Astrocytic adrenoceptors and learning: alpha1-adrenoceptors.

Noradrenergic receptors are expressed on both on astrocytes and neurons and noradrenergic activation of astrocytic beta(2)- and beta(3)-adrenoceptors are necessary for memory consolidation. In this paper, we marshal evidence for astrocytic alpha(1)-adrenoceptor involvement in memory consolidation. We examine the role of alpha(1)-adrenoceptors in hippocampal and mesopallial (cortical) memory processing using a discriminative avoidance task in the day-old chick. The selective alpha(1)-adrenoceptor agonist, methoxamine, caused the consolidation of weakly-reinforced memory at the time of transition of short-term to intermediate memory and at the time of transition of intermediate to long-term memory. The selective antagonist prazosin prevented memory consolidation at these two times. Blockade of memory by injection of an alpha(2)-adrenoceptor agonist into the LoC could be overcome by mesopallial or hippocampal injection of alpha(1)-, beta(2)- and beta(3)-adrenoceptor agonists. The results of studies where we challenged the ability of methoxamine to promote consolidation by pre-administration of astrocytic metabolic inhibitors of glycogenolysis or oxidative metabolism, suggest that the alpha(1)-adrenoceptor effect is astrocytic. This conclusion is supported by the finding that co-administration of suboptimal doses of methoxamine and thrombin have an additive effect on promoting consolidation. Thrombin causes a calcium response in cultured chick astrocytes but not in neurons. Thrombin, like methoxamine, promotes consolidation at the transition points between short-term, intermediate memory and long-term memory stages. Thrombin enhancement of memory consolidation is blocked by an alpha(1)-adrenoceptor antagonist but not by antagonists of beta(2)- or beta(3)-adrenoceptors. In summary, noradrenaline activation of alpha(1)-adrenoceptors is necessary for consolidation from both short-term and intermediate memory in both the hippocampus and the mesopallium in the chick. Evidence is presented suggesting that the memory consolidating action of alpha(1)-adrenoceptor stimulation results from receptors located on astroctyes and involves an increase in free cytosolic calcium from internal stores.

The effect of hypoxia on the functional and structural development of the chick brain.

Decreased oxygen availability during gestation is linked with altered structural development of the brain and cognitive deficits after birth. Prehatch hypoxia can induce gross neuropathology such as brain lesions or more subtle injury including selective neuronal cell loss, white matter injury and gliosis. In the current study we used the developing chick embryo to determine whether 24h of hypoxia at different prehatch ages, embryonic day 10, 12 or 14 (E10, E12 or E14), resulted in an alteration in neuronal cell number or astrocyte density in brain areas associated with learning and memory. Twenty-four hours of hypoxia (14% oxygen) commencing at E10 resulted in an increase in the density of GFAP-positive astrocytes in the medial striatum (MSt) (P<0.05) and a significant reduction in the number of NeuN-positive neuronal nuclei in the intermediate medial mesopallium (IMM) (P<0.02). Hypoxia at E14 resulted in an increase in GFAP immunoreactivity in the hippocampus (P < or = 0.02) and a significant decrease in the number of NeuN-positive cells in the IMM (P<0.04). Memory was tested soon after hatch using a bead discrimination learning task and results showed that E10 hypoxia significantly reduced short-term memory, which subsequently affected all stages of memory formation (P<0.001), whereas 24h of hypoxia at E14 did not alter short-term memory, but impaired consolidation into long-term memory (P<0.02). Interestingly, 24h of hypoxia at E12 did not alter GFAP immunoreactivity or NeuN-positive cells, nor did it result in memory deficits. We find that an alteration in the number or a disruption in the normal development of astrocytes and neurons significantly affects memory formation and consolidation in the young chick.

Inhibition of Abeta aggregation and neurotoxicity by the 39-kDa receptor-associated protein.

Aggregation of beta-amyloid protein (Abeta) to form oligomers is considered to be a key step in generating neurotoxicity in the Alzheimer's disease brain. Agents that bind to Abeta and inhibit oligomerization have been proposed as Alzheimer's disease therapeutics. In this study, we investigated the binding of fluorescein-labeled Abeta(1-42) (FluoAbeta(1-42)) to SH-SY5Y neuroblastoma cells and examined the effect of the 39-kDa receptor-associated protein (RAP), on the Abeta cell interaction. FluoAbeta(1-42) bound to the cells in a punctate pattern. Surprisingly, when RAP was added to the incubations, FluoAbeta(1-42) and RAP were found to be co-localized on the cell surface, suggesting that RAP and Abeta may bind to each other. Experiments using the purified proteins confirmed that a RAP-Abeta complex was stable and resistant to sodium dodecyl sulfate. RAP also inhibited Abeta oligomerization. We next examined whether RAP could inhibit the neurotoxic effects of Abeta. Addition of Abeta(1-42) to SH-SY5Y cells caused an increase in intracellular Ca2+ that was inhibited by treatment of the Abeta peptide with RAP. RAP also blocked an Abeta-induced inhibition of long-term memory consolidation in 1-day-old chicks. This study demonstrates that RAP binds to Abeta and is an inhibitor of the neurotoxic effects of Abeta.

Memory loss caused by beta-amyloid protein is rescued by a beta(3)-adrenoceptor agonist.

Accumulation of the neurotoxic beta-amyloid protein (Abeta) in the brain is a key step in the pathogenesis of Alzheimer's disease (AD). Although transgenic mouse models of AD have been developed, there is a clear need for a validated animal model of Abeta-induced amnesia which can be used for toxicity testing and drug development. Intracranial injections of Abeta(1-42) impaired memory in a single trial discriminative avoidance learning task in chicks. Memory inhibition was closely associated with the state of aggregation of the Abeta peptide, and a scrambled-sequence of Abeta(1-42) peptide failed to impair memory. Abeta had little effect on labile (short-term and intermediate) memory, but blocked consolidation of memory into long-term storage mimicking the type of anterograde amnesia that occurs in early AD. Since noradrenaline exerts a modulatory influence on labile memory in the chick, we examined the effects of two beta-adrenoceptor (AR) agonists on Abeta-induced amnesia. A beta(3)-AR agonist (CL316243), but not a beta(2)-AR agonist, rescued Abeta-induced memory loss, suggesting the need for further studies on the role of beta(3)-ARs in AD.

Ultrasound exposure of the foetal chick brain: effects on learning and memory.

Ultrasound imaging of the brain is routinely used to monitor the development and resolution of brain lesions among premature and compromised newborn human babies. However, animal studies have shown that ultrasound can cause damage to developing foetal and neonatal tissues. In this study we investigated if ultrasound of the chick brain can lead to learning and memory impairment after hatch. We exposed the brains of chicks on day 19 of a 21 day incubation period to 5 or 10 min of B-mode, or to 1, 2, 3, 4 or 5 min of pulsed Doppler ultrasound in ovo. Learning and memory function were assessed at day 2 post-hatch. Our results show that B-mode exposure at E19 does not affect memory function. On the other hand, 2h after training, significant memory impairment occurred following 4 and 5 min of pulsed Doppler exposure at E19. In separate groups of chicks, short-, intermediate- and long-term memory was equally impaired suggesting an inability to learn. Further, the chicks were still unable to learn with a second training session 5 min after completion of the initial testing. These results demonstrate that extended exposure to pulsed Doppler ultrasound can adversely affect cognitive function in the chick when exposure occurs close to the time of hatch.

Astrocytes and interneurons in memory processing in the chick hippocampus: roles for G-coupled protein receptors, GABA(B) and mGluR1.

Glutamate and GABA acting at mGluR1 and GABA(B) receptors, respectively, have roles in memory processing in the hippocampus up to 35 min after bead discrimination learning in the young chick. Activation of mGluR1 receptors is important at 2.5 and 30 min after training, but modulation of these receptors between these two times has no effect on memory. This timing is similar to the action of glutamate on NMDA receptors. The GABA(B) antagonist, phaclofen, and the inhibitor of astrocytic oxidative metabolism, fluoroacetate, inhibited memory when injected between 2.5 and 30 min. Paradoxically, a high dose of the GABA(B) agonist, baclofen, also inhibited memory, but a low dose promoted memory consolidation--an effect possibly caused by too much information and loss of the 'message'. These results are interpreted in terms interactions between interneurons, astrocytes and pyramidal cells and demonstrate the importance of all cell types in memory processing in the hippocampus.

What learning in day-old chickens can teach a neurochemist: focus on astrocyte metabolism.

The learning process sets in motion a prolonged, reproducible, and complicated pattern of brain activation, which provides information about biochemical reactions in activated brain. Study of this pattern during one-trial aversive bead discrimination in day-old chick is facilitated by precise timing of sequential metabolic events occurring between a 10-s learning period, in which the chicks learn to associate a red bead with aversive taste, and memory consolidation, indicated by unwillingness to peck at untainted red beads while freely pecking at corresponding blue beads. Inhibition of learning by metabolic inhibitors and restoration of memory by specific substrates at specific times allow determination of specific metabolic events and their neuronal or astrocytic localization. Downstream metabolism of glycogen and of glucose to pyruvate/lactate is segregated into separate pools. Glucose metabolism via pyruvate dehydrogenation provides energy in both neurons and astrocytes and may include gap junction-mediated lactate transport into astrocytes. A key role is played by glycogenolysis, stimulated by beta2-adrenergic and/or 5-HT2-receptor stimulation along with alpha2-adrenergic stimulation of glycogen synthesis. The importance of glycogen reflects that it selectively supports de novo synthesis of transmitter glutamate by combined pyruvate dehydrogenation and carboxylation in astrocytes.

Rescue of Abeta(1-42)-induced memory impairment in day-old chick by facilitation of astrocytic oxidative metabolism: implications for Alzheimer's disease.

Administration of small oligomeric beta-amyloid (Abeta)(1-42) 45 min before one-trial bead discrimination learning in day-old chicks abolishes consolidation of learning 30 min post-training (Gibbs et al. Neurobiol. Aging, in press). Administration of the beta3-adrenergic agonist CL316243, which specifically stimulates astrocytic but not neuronal glucose uptake, rescues Abeta impaired memory. Weakly reinforced training can be consolidated by various metabolic substrates and we have demonstrated neuronal dependence on oxidative metabolism of glucose soon after training versus astrocytic glucose dependence 20 min later. Based on these findings we examined whether different metabolic substrates were able to counteract memory inhibition by Abeta(1-42). Although lactate, the medium-chain fatty acid octanoate, and the ketone body beta-hydroxybutyrate consolidated weakly reinforced training when injected close to learning, none of them were able to salvage Abeta-impaired memory; at this early time. All three metabolites and the astrocytic-specific acetate consolidated weak learning and rescued Abeta-impaired memory when injected 10-20 min post-training. However, neither glucose nor insulin rescued memory when injected at 20 min. Rescue of memory by providing astrocytes with alternative substrates for oxidative metabolism suggests that Abeta(1-42) exerts its amnestic effects specifically by impairing astrocytic glycolysis.

Importance of adrenergic receptors in prenatally induced cognitive impairment in the domestic chick.

In the domestic chick, mild hypoxia (24h of 14% oxygen) at two stages of embryonic development results in post-hatch memory deficiencies tested using a discriminated bead avoidance task. The nature of the memory loss depends on the gestational age at which the hypoxia occurs. Hypoxia on embryonic day 10 (E10) of a 21 day incubation results in chicks with no short-term memory 10 min after training, whereas hypoxia on day 14 (E14) results in chicks with good labile memory 30 min after training but no consolidation of memory into permanent storage (120 min). Hypoxia at E14 is associated with increased plasma levels of noradrenaline and therefore we suggest that altered catecholamine exposure within the brain contributes to cognitive problems by modifying the responsiveness of brain beta-adrenoceptors. In ovo administration of noradrenaline, or the beta(2)-adrenoceptor agonist formoterol, at E14 had the same effect on memory consolidation as hypoxia. Following hypoxia at E14, memory could be rescued after training by central injection of a beta(3)-adrenoceptor agonist, but not by a beta(2)-adrenoceptor agonist. The differences in the responsiveness of memory processing to beta(2)-adrenoceptor agonists suggests alterations to the receptors or downstream of the receptor activation. However, both types of beta-adrenoceptor agonists rescued memory in E10 treated chicks implying that at this age hypoxia does not affect the receptors. In summary, hypoxia or increased levels of stress hormones during incubation alters beta-adrenoceptor responsiveness; the outcome of the insult depends upon the cellular developmental processes at a given embryonic stage.