Chronic dietary changes in n-6/n-3 polyunsaturated fatty acid ratios cause developmental delay and reduce social interest in mice.

Polyunsaturated fatty acids (PUFAs) are one of the main cellular building blocks, and dietary changes in PUFA composition are proposed as a potential route to influence brain development. For example, initial studies indicated that there is a relation between blood omega-6(n-6)/omega-3(n-3) PUFA ratios and neurodevelopmental disease diagnosis. To study the consequences of dietary n-6/n-3 PUFA ratio changes, we investigated the impact of a n-3 supplemented and n-3 deficient diet in developing BTBR T + Itpr3tf/J (BTBR) - a mouse inbred strain displaying Autism Spectrum Disorder (ASD)-like symptomatology - and control C57BL/6J mice. This study showed that pre- and postnatal changed dietary n-6/n-3 ratio intake has a major impact on blood and brain PUFA composition, and led to delayed physical development and puberty onset in both strains. The PUFA induced developmental delay did not impact adult cognitive performance, but resulted in reduced social interest, a main ASD behavioral feature. Thus, both chronic dietary n-3 PUFA supplementation and depletion may not be beneficial.

Food for thought: dietary changes in essential fatty acid ratios and the increase in autism spectrum disorders.

The last decades have shown a spectacular and partially unexplained rise in the prevalence of autism spectrum disorders (ASD). This rise in ASD seems to parallel changes in the dietary composition of fatty acids. This change is marked by the replacement of cholesterol by omega-6 (n-6) fatty acids in many of our food products, resulting in a drastically increased ratio of omega-6/omega-3 (n-6/n-3). In this context, we review the available knowledge on the putative role of fatty acids in neurodevelopment and describe how disturbances in n-6/n-3 ratios may contribute to the emergence of ASDs. Both clinical and experimental research is discussed. We argue that a change in the ratio of n-6/n-3, especially during early life, may induce developmental changes in brain connectivity, synaptogenesis, cognition and behavior that are directly related to ASD.

Cellular mechanisms of burst firing-mediated long-term depression in rat neocortical pyramidal cells.

During wakefulness and sleep, neurons in the neocortex emit action potentials tonically or in rhythmic bursts, respectively. However, the role of synchronized discharge patterns is largely unknown. We have recently shown that pairings of excitatory postsynaptic potentials (EPSPs) and action potential bursts or single spikes lead to long-term depression (burst-LTD) or long-term potentiation, respectively. In this study, we elucidate the cellular mechanisms of burst-LTD and characterize its functional properties. Whole-cell patch-clamp recordings were obtained from layer V pyramidal cells in somatosensory cortex of juvenile rats in vitro and composite EPSPs and EPSCs were evoked extracellularly in layers II/III. Repetitive burst-pairings led to a long-lasting depression of EPSPs and EPSCs that was blocked by inhibitors of metabotropic glutamate group 1 receptors, phospholipase C, protein kinase C (PKC) and calcium release from the endoplasmic reticulum, and that required an intact machinery for endocytosis. Thus, burst-LTD is induced via a Ca2+- and phosphatidylinositol-dependent activation of PKC and expressed through phosphorylation-triggered endocytosis of AMPA receptors. Functionally, burst-LTD is inversely related to EPSP size and bursts dominate single spikes in determining the sign of synaptic plasticity. Thus burst-firing constitutes a signal by which coincident synaptic inputs are proportionally downsized. Overall, our data thus suggest a mechanism by which synaptic weights can be reconfigured during non-rapid eye movement sleep.

Firing mode-dependent synaptic plasticity in rat neocortical pyramidal neurons.

Pyramidal cells in the mammalian neocortex can emit action potentials either as series of individual spikes or as distinct clusters of high-frequency bursts. However, why two different firing modes exist is largely unknown. In this study, we report that in layer V pyramidal cells of the rat somatosensory cortex, in vitro associations of EPSPs with spike bursts delayed by +10 msec led to long-term synaptic depression (LTD), whereas pairings with individual action potentials at the same delay induced long-term potentiation. EPSPs were evoked extracellularly in layer II-III and recorded intracellularly in layer V neurons with the whole-cell or nystatin-based perforated patch-clamp technique. Bursts were evoked with brief somatic current injections, resulting in three to four action potentials with interspike frequencies of approximately 200 Hz, characteristic of intrinsic burst firing. Burst-firing-associated LTD (Burst-LTD) was robust over a wide range of intervals between -100 and +200 msec, and depression was maximal (approximately 50%) for closely spaced presynaptic and postsynaptic events. Burst-LTD was associative and required concomitant activation of low voltage-activated calcium currents and metabotropic glutamate receptors. Conversely, burst-LTD was resistant to blockade of NMDA receptors or inhibitory synaptic potentials. Burst-LTD was also inducible at already potentiated synapses. We conclude that intrinsic burst firing represents a signal for resetting excitatory synaptic weights.