Trends in Neurosciences
ReviewA vitamin for the brain
Introduction
Since its discovery in 1913 [1], vitamin A has been closely tied to the function of the CNS, initially from the discovery of its requirement for vision and soon after from the importance of vitamin A in embryonic development in both the eye and brain. The primary mechanism by which vitamin A regulates CNS development, as well as much of its action in the body, is through its oxidation to the active metabolite, retinoic acid (RA; Figure 1). Its function in the embryonic CNS includes two crucial actions: (i) induction of neurogenesis and (ii) control of neuronal patterning [2]. The latter includes patterning along the anterior–posterior axis, where it may function as a morphogen, determining cell fate according to concentration. The concentration dependence of the effects of RA and its action in regulating patterning through the formation of gradients results in high embryonic sensitivity to disruption when RA levels are too low (deficiency syndrome) or too high (teratogenicity). A number of factors that shape the developing CNS later function in the adult brain to regulate neuroplasticity, and RA is no exception in its action on the adult hippocampus olfactory bulb, and hypothalamus. Because of its key roles in these processes, it is unsurprising that RA function is also implicated in several brain disorders. Some of the new findings in these fields are discussed below.
Section snippets
Neuronal plasticity homeostasis in the hippocampus
Hippocampal long-term potentiation (LTP) and long-term depression (LTD), believed to be essential components of hippocampal-dependent memory, are both dependent on vitamin A and RA [3]. Research on such synaptic effects has continued and recent studies in which a dominant-negative retinoic acid receptor (RAR)α was expressed in mouse forebrain revealed impaired LTP and AMPA receptor (AMPAR)-mediated synapse transmission in the hippocampus, together with reduced social recognition and spatial
RA as part of the seasonal switch in the hypothalamus
The hypothalamus is the primary region of the brain that regulates reproductive status, hormone release, feeding, and energy balance. Recent studies using a seasonal switch to manipulate hypothalamic function (Box 1) have pointed to a crucial role for RA in this region. Certainly many components of the RA signaling pathway are expressed in the hypothalamus (Figure 3) 31, 32, 33. Expression is predominantly localized to three main regions: the arcuate nucleus, known to regulate feeding behavior
Vitamin A for a healthy brain
The World Health Organization (WHO) includes vitamin A deficiency as a major cause of serious illnesses in developing countries [WHO (2002) The World Health Report, http://www.who.int/whr/2002/en/]. Such illnesses include blindness, and increases in susceptibility to malaria and diarrheal diseases, as well as fetal loss, low birth weight, and infant mortality. Its importance for neurological disorders is less well established at this time. Nevertheless, VAD studies in rodents have pointed to
Vitamin A in the brain: what the future may hold
Many questions remain unanswered regarding RA action in the brain (Box 2) and it is very likely that its influence extends beyond the brain regions detailed in this review. Hints of these roles in the cortex were revealed by studies indicating that RARβ is an intermediary between delta oscillations and the slow-wave sleep electroencephalogram [89], probably in part through modulation of dopamine signaling [90]. As already discussed, vitamin A is necessary for the rhythms of the brain and new
Acknowledgments
We thank Ashley Bird for assistance with Figure 1, Figure 2 and the Biological Sciences Research Council for financial support of part of this work (Grant BB/G014272/1).
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