In order to determine brain and behavioral sensitivity of nutrients that may serve as inductive signals during early development, we altered choline availability to rats during 7 time frames spanning embryonic day (ED) 6 through postnatal day (PD) 75 and examined spatial memory ability in the perinatally-treated adults. Two sensitive periods were identified, ED 12–17 and PD 16–30, during which choline supplementation facilitated spatial memory and produced increases in dendritic spine density in CA1 and dentate gyrus (DG) regions of the hippocampus while also changing the dendritic fields of DG granule cells. Moreover, choline supplementation during ED 12–17 only, prevented the memory decline normally observed in aged rats. These behavioral changes were strongly correlated with the acetylcholine (ACh) content of hippocampal slices following stimulated release. Our data demonstrate that the availability of choline during critical periods of brain development influences cognitive performance in adulthood and old age, and emphasize the importance of perinatal nutrition for successful cognitive aging.
Choline supplementation during fetal development [embryonic days (E) 11-17] permanently enhances memory performance in rats. To characterize the neurochemical mechanisms that may mediate this effect, we investigated the development of indices of the cholinergic system in the hippocampus: choline acetyltransferase (ChAT), acetylcholinesterase (AChE), synthesis of acetylcholine (ACh) from choline transported by high-affinity choline uptake (HACU), and potassium-evoked ACh release. During E11-E17, Sprague-Dawley pregnant rats consumed 0 [choline-deficient (ChD)], 1.3 [control (ChC)], and 4.6 [choline-supplemented (ChS)] mmol/(kg x day) of choline, respectively. On postnatal days 17 and 27, hippocampi of the ChD animals had the highest AChE and ChAT activities, and increased synthesis of ACh from choline transported by HACU, concomitant with reductions of tissue ACh content relative to the ChC and ChS rats and an inability to sustain depolarization-evoked ACh release relative to the ChS animals. In contrast, AChE and ChAT activities, and ACh synthesized from choline transported by HACU, were lowest in ChS rats whereas depolarization-evoked ACh release was the highest. This pattern of changes suggests that the hippocampus of the ChD animals is characterized by fast ACh recycling and efficient choline reutilization for ACh synthesis, presumably to maintain adequate ACh release despite the decrease of the ACh pool, whereas in the ChS animals ACh turnover and choline recycling is slower while the evoked release of ACh is high. Together, the data show a complex adaptive response of the hippocampal cholinergic system to prenatal choline availability and provide a novel example of developmental plasticity in the nervous system governed by the supply of a single nutrient.
SUMMARY
Type 1 diabetes is caused by autoimmune-mediated β cell destruction leading to insulin deficiency. The histone deacetylase SIRT1 plays an essential role in modulating several age-related diseases. Here we describe a family carrying a mutation in the SIRT1 gene, in which all five affected members developed an autoimmune disorder: four developed type 1 diabetes, and one developed ulcerative colitis. Initially, a 26-year-old man was diagnosed with the typical features of type 1 diabetes, including lean body mass, autoantibodies, T cell reactivity to β cell antigens, and a rapid dependence on insulin. Direct and exome sequencing identified the presence of a T-to-C exchange in exon 1 of SIRT1, corresponding to a leucine-to-proline mutation at residue 107. Expression of SIRT1-L107P in insulin-producing cells resulted in overproduction of nitric oxide, cytokines, and chemokines. These observations identify a role for SIRT1 in human autoimmunity and unveil a monogenic form of type 1 diabetes.
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