The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca2+-permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation.

The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer’s disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca2+ and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca2+-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.

The purpose of this study was to examine the rates of substrate oxidation in lean and obese women during short-duration, high-intensity exercise and to examine the effects of a 16-week exercise training program on substrate oxidation during 30 min of exercise in lean and obese individuals. Fat and carbohydrate oxidation were measured in 8 non-obese (Non-Ob), 11 lower-body obese (LBO) and 12 upper-body obese (UBO) women at rest and during 30 min of treadmill exercise at 70% of peak oxygen uptake. The obese women participated in 16 weeks of aerobic training (3 times per week at 70% of maximum oxygen uptake). Total fat and carbohydrate oxidation were measured using indirect calorimetry. The respiratory exchange ratio (R) was similar between groups at rest and was found to decrease throughout the exercise session (P< 0.01). Fat oxidation was greater at 15 min of exercise than at rest (P<0.01) but did not increase significantly more at 30 min of exercise. Obese women had significantly greater fat oxidation (both absolute concentrations and when expressed per kg of fat free mass, FFM) at 30 min of exercise than the Non-Ob women [Non-Ob 23.5 (3.7) micromol.kg FFM(-1).min(-1), LBO 35.2 (3.1) micromol.kg FFM(-1).min(-1), UBO 33.2 (2.6) micromol.kg FFM(-1).min(-1); P<0.01]. Carbohydrate oxidation also increased (P < 0.01) in response to exercise, but no group differences were found. The pattern of fat distribution (LBO vs UBO) did not affect the resting or exercise fat oxidation (P=NS). Sixteen weeks of aerobic exercise did not result in significant changes in resting or exercise fat oxidation in the obese women (n = 10; P=NS), but did significantly increase carbohydrate oxidation [pretraining 8.6 (1.4) micromol.kg FFM(-1), post-training 13.6 (2.1) micromol.kg FFM(-1).min(-1); P<0.01]. Unlike earlier studies, this shorter-duration, higher-intensity exercise resulted in a greater whole-body fat oxidation in the obese women than in the Non-Ob women, and exercise training did not result in any changes in fat oxidation, but did increase exercise carbohydrate oxidation.

α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) are the primary conduits of excitatory synaptic transmission. AMPARs are predominantly Ca-impermeable in the matured excitatory synapse, except under certain circumstances. Growing evidence implicates the Ca permeability of AMPARs in the regulation of long-term synaptic plasticity and in the pathophysiology of several neurological disorders. Therefore, the Ca conductance of AMPARs may have both physiological and pathological roles at synapses. However, our understanding of the role of Ca permeable AMPARs (CP-AMPARs) in Alzheimer's disease is limited. Here we discuss insights into the potential CP-AMPAR mediated pathophysiology of Alzheimer's disease, including: 1. Ca-mediated aberrant regulation of synapse weakening mechanisms, and 2. neuronal network dysfunction in the brain. Consideration of CP-AMPARs as primary drivers of pathophysiology could help in understanding synaptopathologies, and highlights the potential of CP-AMPARs as therapeutic targets in Alzheimer's disease. This article is part of the Special Issue entitled 'Ionotropic glutamate receptors'.