Protective Effects of Prenatal Choline Supplementation on Seizure-Induced Memory Impairment

Prenatal choline supplementation attenuates neuropathological response to status epilepticus in the adult rat hippocampus

“…Compared to control rats, adult offspring of dams that were fed a choline-enriched diet for just 1 week, mid-gestation, responded to SE with: 1) reduced hippocampal histopathology, 2) robust protection against loss of GAD65 protein and mRNA expression, 3) marked attenuation of dentate cell proliferation, 4) dramatic reduction of GFAP mRNA expression (with a tendency for GFAP protein to be reduced as well), and 5) an altered pattern of growth factor expression. These data are particularly important because prior work has shown a savings in hippocampal-dependent learning and memory at a similar time point following excitotoxin-induced SE in prenatally choline-supplemented rats (Yang et al, 2000;Holmes et al, 2002), suggesting that increased choline availability to the fetus may alter neural development such that the adult brain is protected from SE-induced damage and cognitive impairment. While these data do not rule out the possibility that choline supplements may have neuroprotective actions at other periods, we know that choline has profound memoryenhancing effects if it is supplemented on ED12-17 or PD15-30, but not at other developmental or adult timeframes (Meck & Williams, 2003).…”

“…All dams were individually housed in clear polycarbonate cages (27.9×27.9×17.8 cm) that were individually ventilated, and the colony was maintained at 21°C on a 12-h light/dark cycle with lights on at 7 a.m. Dams were fed a control diet ad libitum (AIN76-A from Dyets, American Institute of Nutrition, ICN, Nutritional Biochemical, Cleveland, Ohio; 1.1 g/kg choline chloride substituted for choline bitartrate). Prenatal diet treatments were the same as those used in studies showing memory enhancing and memory protecting effects of prenatal choline supplementation (Meck et al, 1988(Meck et al, , 1989Yang et al, 2000;Holmes et al, 2002;Meck & Williams, 2003). On the morning of ED11 to the morning of ED18 , pregnant dams were either given ad libitum access to a control diet (n = 14) or a choline supplemented diet (n = 6).…”

“…The selection of this particular time point (16 days post-KA/saline treatment) was based on 1) the findings reported in Hattiangady et al (2004) that showed robust increases in hippocampal neurogenesis 16 days following an analogous KA treatment, and 2) prenatal choline supplementation's protection against memory deficits was observed 1-2 weeks after excitotoxin-induced status epilepticus (Yang et al, 2000;Holmes et al, 2002), which approximates the current time window we have chosen. The hippocampus from one half-brain was immediately dissected for mRNA and protein analyses and stored at −80° C until assayed.…”

“…To detect changes in dentate cell proliferation as a result of KA-induced SE, we visualized cells immunopositive for the cell division marker, BrdU, administered 5-16 days post-SE to capture the time window during which savings in spatial learning and memory following excitotoxin-induced SE have been observed with prenatal choline supplementation (Yang et al, 2000;Holmes et al, 2002). The amount of cell proliferation after SE that we captured with our 10-day BrdU regimen yielded a very high density of immunostaining.…”

“…Prenatal choline supplementation also enhances several features of adult hippocampal plasticity known to influence learning and memory function, such as increased baseline levels of neurogenesis, brain-derived neurotrophic factor (BDNF) (Glenn et al, 2007) and nerve growth factor (NGF) (Sandstrom et al, 2002); a reduced threshold to induce long-term potentiation (Pyapali et al, 1998;Jones et al, 1999); and enhanced depolarizationinduced mitogen-activated protein kinase (MAPK) and cAMP-response element binding protein (CREB) activation (Mellott et al, 2004). Enhanced hippocampal plasticity may underlie prenatal choline supplementation's neuroprotection of the hippocampus, rendering the hippocampus better able to withstand or recover from the deleterious effects of a neural insult.Given that prenatal choline supplementation has been shown to protect against seizure-induced memory loss on a hippocampal-dependent task (Yang et al, 2000;Holmes et al, 2002), we hypothesized that prenatal choline supplementation alters the neurophysiological response of the hippocampus to SE. To investigate this, we used a model of excitotoxic injury to examine whether prenatal choline availability modulates a variety of markers known to change shortly after SE, including hippocampal histopathology, glutamic acid decarboxylase (GAD) expression, dentate cell proliferation, neurogenesis, astrogliosis, and growth factor content.…”