KIBRA anchoring the action of PKMζ maintains the persistence of memory.

How can short-lived molecules selectively maintain the potentiation of activated synapses to sustain long-term memory? Here, we find kidney and brain expressed adaptor protein (KIBRA), a postsynaptic scaffolding protein genetically linked to human memory performance, complexes with protein kinase Mzeta (PKMζ), anchoring the kinase's potentiating action to maintain late-phase long-term potentiation (late-LTP) at activated synapses. Two structurally distinct antagonists of KIBRA-PKMζ dimerization disrupt established late-LTP and long-term spatial memory, yet neither measurably affects basal synaptic transmission. Neither antagonist affects PKMζ-independent LTP or memory that are maintained by compensating PKCs in ζ-knockout mice; thus, both agents require PKMζ for their effect.

Early-life propofol exposure does not affect later-life GABAergic inhibition, seizure induction, or social behavior.

The early developing brain is especially vulnerable to anesthesia, which can result in long lasting functional changes. We examined the effects of early-life propofol on adult excitatory-inhibitory balance and behavior. Postnatal day 7 male mice were exposed to propofol (250 mg/kg i.

Exposure to Sevoflurane, But Not Ketamine, During Early-life Brain Development has Long-Lasting Effects on GABA Receptor Mediated Inhibitory Neurotransmission.

Understanding the different mechanisms associated with different anesthetic targeted receptors is critical towards identifying accurate long-term outcome measures as a result of early-life anesthetic exposure. We examined changes in GABA receptor mediated neurotransmission by a predominately GABA receptor targeted anesthetic, sevoflurane or a predominately NMDA receptor targeted anesthetic, ketamine. Postnatal day 7 male mice were exposed to sevoflurane or ketamine and examined as adults for changes in inhibitory neurotransmission and its associated change in induced seizure activity.

Persistent increases of PKMζ in memory-activated neurons trace LTP maintenance during spatial long-term memory storage.

PKMζ is an autonomously active PKC isoform crucial for the maintenance of synaptic long-term potentiation (LTP) and long-term memory. Unlike other kinases that are transiently stimulated by second messengers, PKMζ is persistently activated through sustained increases in protein expression of the kinase. Therefore, visualizing increases in PKMζ expression during long-term memory storage might reveal the sites of its persistent action and thus the location of memory-associated LTP maintenance in the brain.

Antisense Oligodeoxynucleotide Perfusion Blocks Gene Expression of Synaptic Plasticity-related Proteins without Inducing Compensation in Hippocampal Slices.

The elucidation of the molecular mechanisms of long-term synaptic plasticity has been hindered by both the compensation that can occur after chronic loss of the core plasticity molecules and by conditions that may not reproduce plasticity. Here we describe a novel method to rapidly suppress gene expression by antisense oligodeoxynucleotides (ODNs) applied to rodent brain slices in an "Oslo-type" interface chamber. The method has three advantageous features: 1) rapid blockade of new synthesis of the targeted proteins that avoids genetic compensation, 2) efficient oxygenation of the brain slice, which is critical for reproducing conditions of long-term synaptic plasticity, and 3) a recirculation system that uses only small volumes of bath solution (< 5 ml), reducing the amount of reagents required for long-term experiments lasting many hours.

Anesthesia and Cognitive Outcome in Elderly Patients: A Narrative Viewpoint.

Better ways to manage preoperative, intraoperative and postoperative care of surgical patients is the bailiwick of anesthesiologists. Although we care for patients of all ages, protecting the cognitive capacity of elderly patients more frequently requires procedures and practices that go beyond routine care for nonelderly adults. This narrative review will consider current understanding of the reasons that elderly patients need enhanced care, and recommendations for that care based on established and recent empirical research.

Succinylcholine and Intracranial Pressure.

Intracranial and Hemodynamic Changes after Succinylcholine Administration in Cats. By Cottrell JE, Hartung J, Giffin JP, and Shwiry B. Anesthesia & Analgesia 1983; 62:1006-9.

Neonatal anesthesia exposure impacts brain microRNAs and their associated neurodevelopmental processes.

MicroRNAs (miRNAs), when subjected to environmental stimuli, can exhibit differential expression. As critical regulators of gene expression, differential miRNA expression has been implicated in numerous disorders of the nervous system. In this study, we focused on the effect of a general anesthetic, as an environmental stimulus, on miRNA expression of the developing brain.

Sevoflurane Blocks the Induction of Long-term Potentiation When Present during, but Not When Present Only before, the High-frequency Stimulation.

Background: This study tests the hypothesis that sevoflurane blocks long-term potentiation only if it is present during the high-frequency stimulation that induces long-term potentiation.

Methods: Long-term potentiation, an electrophysiologic correlate of memory, was induced by high-frequency stimulation and measured as a persistent increase in the field excitatory postsynaptic potential slope in the CA1 region.

Results: Long-term potentiation was induced in the no sevoflurane group (171 ± 58% vs.

Persistent increased PKMζ in long-term and remote spatial memory.

PKMζ is an autonomously active PKC isoform that is thought to maintain both LTP and long-term memory. Whereas persistent increases in PKMζ protein sustain the kinase's action in LTP, the molecular mechanism for the persistent action of PKMζ during long-term memory has not been characterized. PKMζ inhibitors disrupt spatial memory when introduced into the dorsal hippocampus from 1day to 1month after training.

Compensation for PKMζ in long-term potentiation and spatial long-term memory in mutant mice.

PKMζ is a persistently active PKC isoform proposed to maintain late-LTP and long-term memory. But late-LTP and memory are maintained without PKMζ in PKMζ-null mice. Two hypotheses can account for these findings.

Subunit and frequency-dependent inhibition of acid sensing ion channels by local anesthetic tetracaine.

Background: Extracellular acidosis is a prominent feature of multiple pathological conditions, correlating with pain sensation. Acid-sensing ion channels (ASICs), a family of proton-gated cation channels, are distributed throughout the central and peripheral nervous systems. Activation of ASICs, particularly ASIC3 and ASIC1a channels, by acidic pH and the resultant depolarization of nociceptive primary sensory neurons, participates in nociception.

Sevoflurane preconditioning attenuates the fall in adenosine triphosphate levels, but does not alter the changes in sodium and potassium levels during hypoxia in rat hippocampal slices.

Background: Sevoflurane preconditioning improves recovery after hypoxia. Sevoflurane administered before and during hypoxia improved recovery and attenuated the changes in intracellular sodium, potassium, and adenosine triphosphate (ATP) levels during hypoxia. In this study, the authors examine the effects of sevoflurane applied only before hypoxia on sodium, potassium, and ATP.

Metabotropic actions of the volatile anaesthetic sevoflurane increase protein kinase M synthesis and induce immediate preconditioning protection of rat hippocampal slices.

Anaesthetic preconditioning occurs when a volatile anaesthetic, such as sevoflurane, is administered before a hypoxic or ischaemic insult; this has been shown to improve neuronal recovery after the insult. We found that sevoflurane-induced preconditioning in the rat hippocampal slice enhances the hypoxic hyperpolarization of CA1 pyramidal neurons, delays and attenuates their hypoxic depolarization, and increases the number of neurons that recover their resting and action potentials after hypoxia. These altered electrophysiological effects and the improved recovery corresponded with an increase in the amount of a constitutively active, atypical protein kinase C isoform found in brain, protein kinase M zeta (PKMζ).

Developmental disability in the young and postoperative cognitive dysfunction in the elderly after anesthesia and surgery: do data justify changing clinical practice?

The assumption that anesthesia has no serious, long-term, adverse central nervous system consequences may be true for most patients between 6 months and 60 years of age. However, for patients younger than 6 months or older than 60 years, that status quo assumption is under challenge from a growing body of evidence. Fetuses and newborns appear to be at risk because systems that would enable them to fully recover from the effects of more than 2 hours of anesthesia are still in development.

Inhibition of acid sensing ion channel currents by lidocaine in cultured mouse cortical neurons.

Background: Lidocaine is a local anesthetic that has multiple pharmacological effects including antiarrhythmia, antinociception, and neuroprotection. Acid sensing ion channels (ASICs) are proton-gated cation channels that belong to the epithelial sodium channel/degenerin superfamily. Activation of ASICs by protons results in sodium and calcium influx.

Posthypoxic moderate hypothermia improves electrophysiological recovery in the rat hippocampal slice.

Background: Animal studies have shown that prehypoxic or intrahypoxic hypothermia is protective against hypoxic neuronal injury, whereas posthypoxic hypothermia produced divergent findings. This study examined the protective effects of posthypoxic hypothermia on the electrophysiological recovery in the rat hippocampal slice.

Methods: Eighty-three male Sprague-Dawley rats were used after approval of the Institutional Animal Care and Use Committee.

Effects of midazolam on brain injury after transient focal cerebral ischemia in rats*.

The benzodiazepine, midazolam, is commonly used for sedation and anesthesia in the operating room and the intensive care unit where there is a risk of cerebral ischemia. We therefore examined its ability to reduce damage subsequent to cerebral ischemia. Male Wistar rats were randomly assigned to a high-dose midazolam group or a matched vehicle group and a lower dose of midazolam group or a matched vehicle group.