Folate andS-adenosylmethionine modulate synaptic activity in cultured cortical neurons: acute differential impact on normal and apolipoprotein-deficient mice

Abstract

Folate deficiency is accompanied by a decline in the cognitive neurotransmitter acetylcholine and a decline in cognitive performance in mice lacking apolipoprotein E (ApoE-/- mice), a low-density lipoprotein that regulates aspects of lipid metabolism. One direct consequence of folate deficiency is a decline in S-adenosylmethionine (SAM). Since dietary SAM supplementation maintains acetylcholine levels and cognitive performance in the absence of folate, we examined herein the impact of folate and SAM on neuronal synaptic activity. Embryonic cortical neurons from mice expressing or lacking ApoE (ApoE+/+ or -/-, respectively) were cultured for 1 month on multi-electrode arrays, and signaling was recorded. ApoE+/+ cultures displayed significantly more frequent spontaneous signals than ApoE-/- cultures. Supplementation with 166 microm SAM (not normally present in culture medium) increased signal frequency and decreased signal amplitude in ApoE+/+ cultures. SAM also increased the frequency of tightly clustered signal bursts. Folate deprivation reversibly reduced signal frequency in ApoE+/+ cultures; SAM supplementation maintained signal frequency despite folate deprivation. These findings support the importance of dietary supplementation with folate and SAM on neuronal health. Supplementation with 166 microm SAM did not alter signaling in ApoE-/- cultures, which may be a reflection of the reduced SAM levels in ApoE-/- mice. The differential impact of SAM on ApoE+/+ and -/- neurons underscores the combined impact of nutritional and genetic deficiencies on neuronal homeostasis.

Accelerated establishment of mature signaling patterns following stimulation of developing neuronal networks: “learning” versus “plasticity”

“…Data were captured at 3.125 kHz simultaneously accessing 16 channels and 12.5 kHz accessing 4 channels; the latter was used to validate the use of undersampling for the purpose of observing more channels. Prior studies using combinations of excitatory and inhibitory neuronal antagonists have confirmed synaptic origin of signals in these cultures (Serra et al, 2008a,b, 2010; Serra and Shea, 2009).…”

Short-term nutritional folate deficiency in rats has a greater effect on choline and acetylcholine metabolism in the peripheral nervous system than in the brain, and this effect escalates with age

“…Choline- or choline-methionine-deficient diets induce severe depletion of hepatic folate in rats, suggesting that choline deficiency leads to increased utilization of folate to maintain hepatic methionine and S-adenosylmethionine [28–30, 37]. Folate deficiency has recently been reported to reduce brain acetylcholine levels and cause abnormalities of synaptic function in vitro in mice that lack apolipoprotein E [33, 38]. The metabolic relationships among folate, choline, and acetylcholine have been increasingly recognized as important because of the roles of these compounds in brain plasticity and behavior [2–4, 21, 39, 40].…”

Stimulation with a Low-Amplitude, Digitized Synaptic Signal to Invoke Robust Activity within Neuronal Networks on Multielectrode Arrays

“…As described previously (17,2326), long-term (mature) cultures develop spontaneous signals that radiate across large areas of the culture, as evidenced by their simultaneous appearance at multiple electrodes. When recorded, spontaneous signals in our mature cultures exhibited a regular amplitude (40.0 5.0 V) and duration (0.8 0.2sec, mean standard deviation, n = 20 individual signals from 3 cultures from separate experiments).…”