Pharmacological Protection of Synaptic Function, Spatial Learning, and Memory from Transient Hypoxia in Rats

Sun, Miao‐Kun; Xu, Hanlin; Alkon, Daniel L.

doi:10.1124/jpet.300.2.408

Cited by 53 publications

(31 citation statements)

References 39 publications

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“…This raises the question how miR-210, which has previously been associated with hypoxia response 24 , may affect memory. Considering the extreme sensitivity of neural structures and neurons to hypoxia 57 , we suggest small changes to oxygen levels in metabolic activity neurons may induce expression of miR-210, which in turn targets key molecules including asparagine synthetase and actin.…”

Section: Discussionmentioning

confidence: 99%

Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee

et al. 2014

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Increasing evidence suggests small non-coding RNAs (ncRNAs) such as microRNAs (miRNAs) control levels of mRNA expression during experience-related remodelling of the brain. Here we use an associative olfactory learning paradigm in the honeybee Apis mellifera to examine gene expression changes in the brain during memory formation. Brain transcriptome analysis reveals a general downregulation of protein-coding genes, including asparagine synthetase and actin, and upregulation of ncRNAs. miRNA-mRNA network predictions together with PCR validation suggest miRNAs including miR-210 and miR-932 target the downregulated protein-coding genes. Feeding cholesterol-conjugated antisense RNA to bees results in the inhibition of miR-210 and of miR-932. Loss of miR-932 impairs long-term memory formation, but not memory acquisition. Functional analyses show that miR-932 interacts with Act5C, providing evidence for direct regulation of actin expression by an miRNA. An activity-dependent increase in miR-932 expression may therefore control actin-related plasticity mechanisms and affect memory formation in the brain.

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Section: Discussionmentioning

confidence: 99%

Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee

et al. 2014

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“…Consequently, the stimulatory effect elicited by certain position 8 variants at NR2A-containing receptors may reflect their preferential, or sole, occupancy of the putative stimulatory site. Binding to this sight may stabilize the interdimer interface of the NMDAactivated receptor, obviating the desensitization that arises from reorientation of the agonistbound interface (Sun et al, 2002).…”

Section: [M8a] and Con-t[m8q]) Or Partially (Con-t[m8e] Con-t[m8i]mentioning

confidence: 99%

Subtype-selective antagonism of N-methyl-d-aspartate receptor ion channels by synthetic conantokin peptides

2007

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Conantokin-G (con-G), conantokin-T (con-T), a truncated conantokin-R (con-R [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17]), that functions the same as wild-type con-R, and variant sequences of con-T, were chemically synthesized and employed to investigate their selectivities as antagonists of glutamate/glycineevoked ion currents in human embryonic kidney-293 cells expressing various combinations of NMDA receptor (NMDAR) subunits (NR), viz., NR1a/2A, NR1a/2B, NR1b/2A and NR1b/2B. Con-G did not substantially affect ion flow into NR1a,b/NR2A-transfected cells, but potently inhibited cells expressing NR1a,b/NR2B, showing high NR2B selectivity. Con-T and con-R served as nonselective antagonists of all of four NMDAR subunit combinations. C-terminal truncation variants of the 21-residue con-T were synthesized and examined in this regard. While NMDAR ion channel antagonist activity, and the ability to adopt the Ca 2+ -induced α-helical conformation, diminished as a function of shortening the COOH-terminus of con-T, NMDAR subtype selectivity was enhanced in the con-T[1-11], con-T[1-9], and con-T[1-8] variants toward NR2A, NR1b, and NR1b/2A, respectively. Receptor subtype selectivity was also obtained with Met-8 sequence variants of con-T. Con-T[M8A] and con-T[M8Q] displayed selectivity with NR2B-containing subunits, while con-T[M8E] showed enhanced activity toward NR1b-containing NMDAR subtypes. Of those studied, the most highly selective variant was con-T[M8I], which showed maximal NMDAR ion channel antagonism activity toward the NR1a/2A subtype. These studies demonstrate that it is possible to engineer NMDAR subtype antagonist specificity into con-T. Since the subunit composition of the NMDAR varies temporally and spatially in developing brain and in various disease states, conantokins with high subtype selectivities are potentially valuable drugs that may be used at specific stages of disease and in selected regions of the brain.

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“…Moreover, they found long-lasting posthypoxic impaired learning and memory in rats according to a water maze test, without evidence of cellular damage on histological examination, consistent with a transmission defect without structural neuronal damage. 43 Bolay et al 41 found a restored axonal conduction, but a lasting impairment of cortical synaptic transmission by means of intracortically evoked potentials in the rat motorcortex after transient focal ischemia in vivo. In a later study, they showed a long-lasting defect of synaptic transmission in the penumbral region after transient middle cerebral artery occlusion in rats.…”

Section: Evidence Of Presynaptic Failurementioning

confidence: 99%

“…8,35,36 Thereafter, changes in synaptic responses after variable periods of hypoxia or ischemia have been shown frequently in vitro 37,38,39,40 and in vivo, 41,42,43 and several causes of presynaptic and postsynaptic ischemic failure have been postulated.…”

Section: Synaptic Failure In Ischemiamentioning

confidence: 99%

“…48 In several studies, this transmission defect could be demonstrated up to 4 weeks after the ischemic insult and was considered permanent. 48 -51 Sun et al 43 studied the effect of brief hypoxia on the rat hippocampus in vitro as well as in vivo. Two minutes of hypoxia caused a synaptic arrest with elimination of excitatory postsynaptic potentials in vitro.…”

Section: Evidence Of Presynaptic Failurementioning

confidence: 99%

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Ischemic Cerebral Damage

Hofmeijer¹,

Putten²

2012

Stroke

223

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Abstract-In the human brain, Ϸ30% of the energy is spent on synaptic transmission. Disappearance of synaptic activity is the earliest consequence of cerebral ischemia. The changes of synaptic function are generally assumed to be reversible and persistent damage is associated with membrane failure and neuronal death. However, there is overwhelming experimental evidence of isolated, but persistent, synaptic failure resulting from mild or moderate cerebral ischemia. Early failure results from presynaptic damage with impaired transmitter release. Proposed mechanisms include dysfunction of adenosine triphosphate-dependent calcium channels and a disturbed docking of glutamate-containing vesicles resulting from impaired phosphorylation. We review energy distribution among neuronal functions, focusing on energy usage of synaptic transmission. We summarize the effect of ischemia on neurotransmission and the evidence of long-lasting synaptic failure as a cause of persistent symptoms in patients with cerebral ischemia. Finally, we discuss the implications of synaptic failure in the diagnosis of cerebral ischemia, including the limited sensitivity of diffusion-weighted MRI in those cases in which damage is presumably limited to the synapses. (Stroke. 2012;43:607-615.)Key Words: brain metabolism Ⅲ cerebral ischemia Ⅲ synaptic failure T he human brain is metabolically expensive. Although it represents only 2% of the body weight, it accounts for 20% of oxygen consumption and 25% of glucose utilization. 1,2 Cerebral ischemia is a pathological condition in which blood flow to the brain is insufficient to meet these metabolic demands, causing a loss of neuronal function and viability. Ischemia may be focal if a brain artery is occluded or global, for example, after cardiac arrest.In the 1950s, the concept of perfusion thresholds was introduced. 3 It was shown that functional activity became impaired with moderately reduced perfusion (14 -35 mL/100 g/min), along with electroencephalographic and evoked potential disturbances, whereas loss of ion gradients across the plasma membrane and subsequent cell swelling occur at lower perfusion levels Ϸ4.8 to 8.4 mL/100 g/min (Figure 1). [3][4][5] In focal brain ischemia, the brain tissue that is perfused in the flow range between these 2 levels is now called the penumbra. 6 The penumbra is considered structurally intact and viable, but functionally silent. The dysfunction is, in principle, reversible by restoration of blood flow. However, if oxygen and glucose are not resupplied in time, irreversible damage occurs.Knowledge on the distribution of energy usage among different neuronal activities may contribute to understanding the successive loss of cell function and cell damage in cerebral ischemia. In the human brain, Ϸ30% of the energy is spent on synaptic transmission. 7 Disappearance of synaptic activity is the earliest consequence of cerebral ischemia 8 and failure of synaptic transmission has been proposed to account for electric silence in the penumbra. 3,6,8 -10 The changes of syna...

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Pharmacological Protection of Synaptic Function, Spatial Learning, and Memory from Transient Hypoxia in Rats

Cited by 53 publications

References 39 publications

Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee

Neuroligin-associated microRNA-932 targets actin and regulates memory in the honeybee

Subtype-selective antagonism of N-methyl-d-aspartate receptor ion channels by synthetic conantokin peptides

Ischemic Cerebral Damage

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