Defects in neuronal activity of the entorhinal cortex (EC) are suspected to underlie the symptoms of Alzheimer's disease (AD). Whereas neuroprotective effects of docosahexaenoic acid (DHA) have been described, the effects of DHA on the physiology of EC neurons remain unexplored in animal models of AD. Here, we show that DHA consumption improved object recognition (↑12%), preventing deficits observed in old 3xTg-AD mice (↓12%). Moreover, 3xTg-AD mice displayed seizure-like akinetic episodes, not detected in NonTg littermates and partly prevented by DHA (↓50%). Patch-clamp recording revealed that 3xTg-AD EC neurons displayed (i) loss of cell capacitance (CC), suggesting reduced membrane surface area; (ii) increase of firing rate versus injected current (F-I) curve associated with modified action potentials, and (iii) overactivation of glutamatergic synapses, without changes in synaptophysin levels. DHA consumption increased CC (↑12%) and decreased F-I slopes (↓21%), thereby preventing the opposite alterations observed in 3xTg-AD mice. Our results indicate that cognitive performance and basic physiology of EC neurons depend on DHA intake in a mouse model of AD.

Synapse elimination occurs throughout the nervous system during development, and is essential for the formation of neural circuits. The mechanisms underlying synapse elimination in the brain, however, remain largely unknown. Using whole-cell patch-clamp recording in a slice preparation, we examined synaptic refinement at the somatosensory relay synapse (lemniscal synapse) in the ventral basal thalamus of the mouse during postnatal development. At 1 week old, each neuron in the ventral basal thalamus is innervated by multiple lemniscal fibres, as revealed by multiple increments of the synaptic response. By 16 days after birth (P16), the majority of neurons showed an all-or-none response, suggesting a single fibre innervation. In addition to synapse elimination, extensive modifications in synaptic properties occur during the second week after birth. The ratio of AMPA to NMDA component of the synaptic current tripled between P7 and P17. The decay constant of the NMDA component decreased by about 70% between P7 and P17; ifenprodil (3 μM) reduced the NMDA component by about 40% in neurons at P7-9, but was much less effective at P20-24. On the other hand, there was little change in the inward rectification of AMPA component between P11 and P24. Paired-pulse ratios, measured at −70 and +40 mV, were stable between P7 and P24. Whisker deprivation from P5 through P19 had no effect on the elimination or the maturation of the lemniscal synapse. These results suggest that the lemniscal synapse in the ventral basal thalamus undergoes extensive refinement during the second week, and that sensory experience has a rather limited role in this process.

Serotonin (5-HT) is widely implicated in brain functions and diseases. The vertebrate brain is extensively innervated by 5-HT fibres originating from the brain stem, and 5-HT axon terminals interact with other neurones in complex ways. The cellular mechanisms underlying 5-HT function in the brain are not well understood. The present study examined the effect of 5-HT on the responsiveness of neurones in the neocortex. Using patch-clamp recording in acute slices, we showed that 5-HT substantially increased the slope (gain) of the firing rate-current curve in layer 5 pyramidal neurones of the rat prefrontal cortex. The effect of 5-HT on gain is confined to the range of firing rate (0-10 Hz) that is known to be behaviourally relevant. 5-HT also changed current threshold for spike train generation, but this effect was inconsistent, and was independent of the effect on gain. The gain modulation by 5-HT was mediated by 5-HT 2 receptors, and involved postsynaptic mechanisms. 5-HT 2 -mediated gain increase could not be attributed to changes in the membrane potential, the input resistance or the properties of action potentials, but was associated with a reduction of the afterhyperpolarization and an induction of the slow afterdepolarization. Blocking Ca 2+ entry with Cd 2+ increased the gain by itself and blocked 5-HT 2 -mediated gain increase. Buffering [Ca 2+ ] i with 25 mM EGTA also substantially reduced 5-HT 2 -mediated gain increase. Noradrenaline, which blocked the afterhyperpolarization, also induced a moderate increase in gain. Together, our results suggest that 5-HT may regulate the dynamics of cortical circuits through multiplicative scaling. 5-HT plays an important role in the regulation of behaviour. In cats, activity of 5-HT neurones in the brain stem is highest during periods of waking arousal, decreases progressively as the animal falls asleep, and is absent during rapid-eye-movement sleep (Jacobs & Fornal, 1999). Selective depletion of 5-HT in the prefrontal cortex (PFC) of monkeys induces cognitive inflexibility (Clarke et al. 2004); and 5-HT, via 5-HT 2A receptors, has been shown to contribute to working memory in the monkey PFC (Williams et al. 2002). In humans, dysfunction of the brain 5-HT system plays a critical role in depression; and many antidepressants are selective 5-HT uptake blockers, which enhance 5-HT transmission in the brain (Blier & de Montigny, 1999;Delgado, 2000;Bell et al. 2001). Together, such evidence suggests that at the system level, 5-HT facilitates motor and other executive functions of the CNS.The cellular mechanisms underlying brain 5-HT function are not well understood. Early in vivo studies showed that the predominant effect by 5-HT in the cerebral cortex is an inhibition of spontaneous firing (Krnjevic & Phillis, 1963;Reader et al. 1979). Later studies using intracellular recordings in brain slices revealed that 5-HT induces, often in the same cell, both inhibitory and excitatory responses (Segal, 1980;Andrade & Nicoll, 1987;Araneda & Andrade, 1991;Tanaka & North, 1993;Spain...

No abstract