Taking into account abovementioned vitamin

Taking into account abovementioned, vitamin D3 deficiency effects on synaptic neurotransmission can be considered as targeting both Ca2+-independent and Ca2+-dependent processes. Ca2+-independent action of vitamin D3 deficiency is associated with a decrease in the expression of glutamate and GABA transporters that in turn resulted in decreased efficiency of glutamate and GABA uptake. Ca2+-dependent action is associated with a decrease in exocytotic release of glutamate and GABA presumably through malfunctioning of voltage-gated Ca2+ channels. The main finding of this study is the fact that vitamin D3 deficiency affected both excitatory and inhibitory neurotransmission through modulation of Ca2+-independent and Ca2+-dependent presynaptic processes, and thereby can significantly disturb balance of excitation and inhibition despite a unidirectional manner of these alterations. In our model of vitamin D3 deficiency, we used puberty rats, which were kept at the diet up to adulthood. Literature data have underlined that the impact of low vitamin D intake on 516 3 functioning in adults is very different from that in developmental models. Importance of vitamin D supply during brain development was underlined by epidemiological findings, and also low prenatal vitamin D level may be a risk factor for schizophrenia (Cantor-Graae and Selten, 2005). Proper GABA transport is critical during brain development (Kilb, 2012) and the fact that vitamin D3 deficiency provoked changes in GAT-3 transporter expression, exocytotic release and uptake of GABA at puberty period can be taken into account in brain development studies and medications. Vitamin D deficiency affected the lipid composition of intestinal basolateral membranes from chick intestine and the increased cholesterol content caused an increase in the molar ratio cholesterol/phospholipid (Alisio et al., 1997), and also vitamin D deficiency is associated with an increase in circulating cholesterol (Li et al., 2016). Our pervious results obtained using animal model, in which nerve terminals were treated with cholesterol acceptor methyl-beta-cyclodextrin showed that changes in membrane cholesterol concentrations in nerve terminals can modify key characteristics of synaptic transmission (Borisova, 2013). It is difficult to predict and make detailed prognosis about how synaptic transmission alterations can contribute to the neurological disease development and outcomes, aggravation of brain disorders, less resistance to hypoxia/ischemia and worsen stroke recovery, when human organism throughout life underwent even short-term seasonal periods of weak/strong vitamin D deficiency. The changes in synaptic neurotransmission we found in this study can underlie the following neuropathologies linked to vitamin D3 deficiency in epidemiological studies, namely Alzheimer's and Parkinson's disease, dementia, cognitive function impairment, depression, schizophrenia, psychosis, and autism (Annweiler et al., 2013; Knekt et al., 2010).
Conclusions In summary, experimental data obtained using animal model revealed that nutritional vitamin D3 deficiency decreased the initial rates of transporter-mediated L-[14C]glutamate and [3H]GABA uptake by nerve terminals and Ca2+-dependent exocytotic release; changed the expression of EAAC-1 and GAT-3 transporters; whereas the synaptosomal ambient levels and Ca2+-independent transporter-mediated release of L-[14C]glutamate and [3H]GABA were not significantly altered. Vitamin D3 acted as a potent neurosteroid and its deficiency affected both Ca2+-dependent and Ca2+-independent presynaptic processes, disturbed uptake and exocytotic release of glutamate and GABA in a unidirectional manner, and misbalanced excitation and inhibition that in turn can lead to severe neurological consequences. Also, alterations in glutamate parameters, namely decreased EAAC-1 expression and transporter-mediated glutamate uptake, and the upward tendency in transporter-mediated release and ambient glutamate concentration in vitamin D3 deficiency can lead to a more complicated suffering from hypoxia/ischemia and stroke, and also underlie both larger infarct volumes and worsened outcomes in ischemic stroke patients with vitamin D3 deficiency.