Gordon Royle

A role for calcium-permeable AMPA receptors in synaptic plasticity and learning.

A central concept in the field of learning and memory is that NMDARs are essential for synaptic plasticity and memory formation. Surprisingly then, multiple studies have found that behavioral experience can reduce or eliminate the contribution of these receptors to learning. The cellular mechanisms that mediate learning in the absence of NMDAR activation are currently unknown. To address this issue, we examined the contribution of Ca2+-permeable AMPARs to learning and plasticity in the hippocampus. Mutant mice were engineered with a conditional genetic deletion of GluR2 in the CA1 region of the hippocampus (GluR2-cKO mice). Electrophysiology experiments in these animals revealed a novel form of long-term potentiation (LTP) that was independent of NMDARs and mediated by GluR2-lacking Ca2+-permeable AMPARs. Behavioral analyses found that GluR2-cKO mice were impaired on multiple hippocampus-dependent learning tasks that required NMDAR activation. This suggests that AMPAR-mediated LTP interferes with NMDAR-dependent plasticity. In contrast, NMDAR-independent learning was normal in knockout mice and required the activation of Ca2+-permeable AMPARs. These results suggest that GluR2-lacking AMPARs play a functional and previously unidentified role in learning; they appear to mediate changes in synaptic strength that occur after plasticity has been established by NMDARs.

Enhanced LTP of primary afferent neurotransmission in AMPA receptor GluR2-deficient mice

&NA; Ca2+‐permeable‐AMPA receptors (AMPARs) are expressed in the superficial dorsal horn (SDH, laminae I/II) of the spinal cord, the area involved in transmission and modulation of sensory information, including nociception. A possible role of Ca2+‐permeable‐AMPARs in synaptic strengthening has been suggested in postnatal DH cultures, but their role in the long‐lasting activity‐dependent synaptic plasticity of primary afferent neurotransmission in the adult mouse SDH has not been investigated. In the present study the role of Ca2+‐permeable‐AMPARs in the regulation of long‐lasting synaptic plasticity, specifically long‐term potentiation (LTP) and long‐term depression (LTD) in the SDH, was investigated using mice deficient in AMPAR GluR2 subunit. We show here that the GluR2 mutants exhibited no changes in passive membrane properties, but a significant increase in rectification of excitatory postsynaptic currents, the finding suggesting increased expression of Ca2+‐permeable‐AMPARs. In the absence of GluR2, high‐frequency stimulation (HFS) of small‐diameter primary afferent fibers induced LTP that is enhanced and non‐saturating in the SDH at both primary afferent Aδ‐ and/or C‐fibers monosynaptic and polysynaptic pathways, whereas neuronal excitability and paired‐pulse depression were normal. The LTP could be induced in the presence of the NMDA receptor antagonist d‐AP5, and L‐type Ca2+ channel blockers, suggesting that Ca2+‐permeable‐AMPARs are sufficient to induce LTP in the SDH neurons of adult mouse spinal cord. In contrast, the induction of HFS‐LTD is reduced in the SDH of GluR2 mutants. These results suggest an important role for AMPAR GluR2 subunit in regulating synaptic plasticity with potential relevance for long‐lasting hypersensitivity in pathological states.

The effect of three inhaled anesthetics in mice harboring mutations in the GluR6 (kainate) receptor gene.

Combinations of GluR5-GluR7, KA1, and KA2 subunits form kainate receptors, a subtype of excitatory ionotropic glutamate receptors. Isoflurane enhances the action of kainate receptors comprising GluR6 subunits expressed in oocytes. To test whether alterations of the GluR6 subunit gene affect the actions of inhaled anesthetics in vivo, we measured the minimum alveolar concentration of desflurane, isoflurane, and halothane in mice lacking the kainate receptor subunit GluR6 (GluR6 knockout mice) and mice with a dominant negative glutamine/arginine (Q/R) editing mutation in membrane domain 2 of the GluR6 receptor (GluR6 editing mutants), which increases the calcium permeability of kainate receptors containing GluR6Q. We also measured the capacity of isoflurane to interfere with Pavlovian fear conditioning to a tone and to context. Absence of the GluR6 subunit did not change the minimum alveolar concentration of isoflurane, desflurane, or halothane. Possibly, kainate receptors assembled from the remaining kainate receptor subunits compensate for the absent subunits and thereby produce a normal minimum alveolar concentration. A Q/R mutation that dominantly affects kainate receptors containing the GluR6 subunit in mice increased isoflurane minimum alveolar concentration (by 12%; P < 0.01), decreased desflurane minimum alveolar concentration (by 18%; P < 0.001), and did not change halothane minimum alveolar concentration (P = 0.25). These data may indicate that kainate receptors containing GluR6Q subunits differently modulate, directly or indirectly, the mechanism by which inhaled anesthetics cause immobility. The mutations of GluR6 that were studied did not affect the capacity of isoflurane to interfere with fear conditioning.

Acute eosinophilic endomyocarditis: early diagnosis and localisation of the lesion by cardiac magnetic resonance imaging

Cardiac involvement is the main cause of morbidity and mortality in hypereosinophilic syndrome. In a patient with hypereosinophilia and a normal echocardiography, cardiac magnetic resonance imaging (CMR) helped confirm early cardiac involvement by demonstrating a typical pattern of left ventricular subendocardial and papillary muscle involvement. The use of CMR facilitated prompt institution of aggressive therapy and was useful in monitoring response to treatment.

Novel sequence insertion in a Mâori patient with transfusion-dependent β-thalassaemia

Although β‐thalassaemia is common throughout the world, it has not been previously described in Polynesia. We report a novel sequence insertion where homozygosity for the defect results in transfusion‐dependent anaemia. The repeated 45 base pair (bp) insertion causes duplication of the start codon and consequent transcription from the original initiation code would be predicted to lead to the production of an irrelevant seven‐residue peptide, while residual translation from the novel initiation site would result in diminished yields of β‐globin and consequent clinical β+‐thalassaemia.

Racial Variation in Serum Uric Acid Concentration in Pregnancy: a Comparison between European, New Zealand Maori and Polynesian Women

EDITORIAL COMMENT: This paper confirms the findings of the study reported by Carter and Child (Aust NZ J Obstet Gynaecol 1989; 29: 213–214) that serum uric acid values increase during pregnancy. It provides extra data that the serum uric acid values are higher in New Zealand Maori and Pacific Islanders than in New Zealand European women. The authors did not tackle RA Fays hypothesis (Aust NZ J Obstet Gynaecol 1990; 30:141–142) that the rise in serum uric acid in patients with preeclampsia is secondary to placental damage rather than alteration in renal function. None of the patients in this New Zealand study had hypertension or renal disease. The next step is to tell us when women with chronic renal disease, with or without superadded preeclampsia, and who have uric acid values well above the 0.45 mmol/l upper limit of normal, require delivery when tests of fetal well‐being (cardiotocography, blood flow studies) remain within normal limits. When do sustained high uric acid values signal that irreversible renal failure is imminent?

Right ventricular dysfunction and pulmonary hypertension following sub‐massive pulmonary embolism

Persistent right ventricular dysfunction (RVD) and pulmonary hypertension (PHT) are important outcomes following sub‐massive pulmonary embolism (PE). The aims were to determine the rates and factors associated with RVD and/or PHT on echocardiography (ECHO) and the rate of 30‐day and 1‐year all‐cause mortality following sub‐massive PE. Patients who received thrombolysis and non‐thrombolysis were also compared.