The formation of synaptic contacts in human cerebral cortex was compared in two cortical regions: auditory cortex (Heschl's gyrus) and prefrontal cortex (middle frontal gyrus). Synapse formation in both cortical regions begins in the fetus, before conceptual age 27 weeks. Synaptic density increases more rapidly in auditory cortex, where the maximum is reached near postnatal age 3 months. Maximum synaptic density in middle frontal gyrus is not reached until after age 15 months. Synaptogenesis occurs concurrently with dendritic and axonal growth and with myelination of the subcortical white matter. A phase of net synapse elimination occurs late in childhood, earlier in auditory cortex, where it has ended by age 12 years, than in prefrontal cortex, where it extends to midadolescence. Synaptogenesis and synapse elimination in humans appear to be heterochronous in different cortical regions and, in that respect, appears to differ from the rhesus monkey, where they are concurrent. In other respects, including overproduction of synaptic contacts in infancy, persistence of high levels of synaptic density to late childhood or adolescence, the absolute values of maximum and adult synaptic density, and layer specific differences, findings in the human resemble those in rhesus monkeys.
Long-range, directed migration is particularly dramatic in the cerebral cortex, where postmitotic neurons generated deep in the brain migrate to form layers with distinct form and function. In the X-linked dominant human disorder periventricular heterotopia (PH), many neurons fail to migrate and persist as nodules lining the ventricular surface. Females with PH present with epilepsy and other signs, including patent ductus arteriosus and coagulopathy, while hemizygous males die embryonically. We have identified the PH gene as filamin 1 (FLN1), which encodes an actin-cross-linking phosphoprotein that transduces ligand-receptor binding into actin reorganization, and which is required for locomotion of many cell types. FLN1 shows previously unrecognized, high-level expression in the developing cortex, is required for neuronal migration to the cortex, and is essential for embryogenesis.
Metabolic effects of a new ketogenic regimen in which ketonemia is induced by feeding of medium chain triglycerides (MCT) are described, and comparisons are made with effects of the standard high fat ketogenic diet. Eighteen children maintained on the MCT diet for 3 months to 4 years failed to show elevations of serum cholesterol and had only a slight rise in serum total fatty acids, in contrast to the marked hyperlipidemia observed in children on the standard high fat diet. Long term use of the MCT diet did not affect pH of venous blood. Blood glucose fell below 50 mg/100 ml in one-third of the children, the lowest levels being reached 2-3 weeks after the start of the diet. Plasma D(-)-P-hydroxybutyrate (BHB) and acetoacetate rose gradually after institution of diet therapy, maximum levels being reached after about 1 month. Higher levels of BHB and acetoacetate were achieved in children under the age of 10 years (BHB = 4.3 mM 0.6 SEM, acetoacetate = 1.8 mM i 0.3 SEM) than in 1@18 year olds (BHB = 1.6 mM + 0.2 SEM, acetoacetate = 0.57 mM 0.08 SEM). Plasma BHB and acetoacetate levels in children maintained on a 3:l high fat diet were similar to those in children on a 60% MCT diet. Plasma levels of BHB showed a significant correlation with anticonvulsant effect ( P < 0.02). Both the ketonemia and the anticonvulsant action were reversed rapidly by intravenous infusion of glucose.
SpeculationThe anticonvulsant effect of the standard ketogenic diet and of the MCT diet are dependent upon maintenance of blood levels of BHB above 2 mM and of acetoacetate above 0.6 mM. The data suggest that one or both of these compounds either have direct anticonvulsant effects or produce rapidly reversible changes in cerebral metabolism, which in turn affect cerebral excitability.
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