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Limbic system pathologies associated with deficiencies and excesses of the trace elements iron, zinc, copper, and selenium

Adriana Torres-Vega, Bernardo F Pliego-Rivero, Gloria A Otero-Ojeda, Leobardo M Gómez-Oliván, Patricia Vieyra-Reyes
DOI: http://dx.doi.org/10.1111/j.1753-4887.2012.00521.x 679-692 First published online: 1 December 2012

Abstract

Deficiencies of nutrients such as amino acids, vitamins, lipids, and trace elements during gestation and early infanthood have strong deleterious effects on the development of the limbic system; these effects may be irreversible, even when adequate supplementation is provided at later developmental stages. Recent advances in the neurochemistry of biometals are increasingly establishing the roles of the trace elements iron, copper, zinc, and selenium in a variety of cell functions and are providing insight into the repercussions of deficiencies and excesses of these elements on the development of the central nervous system, especially the limbic system. The limbic system comprises diverse areas with high metabolic demands and differential storage of iron, copper, zinc, and selenium. This review summarizes available evidence suggesting the involvement of these trace elements in pathological disorders of the limbic system.

  • copper
  • iron
  • limbic system
  • selenium
  • zinc

INTRODUCTION

Since the beginning of the 20th century, a large body of evidence has accumulated concerning trace elements in living tissues. Early workers in the field, using inaccurate techniques, demonstrated the presence of a large number of trace elements in blood, milk, and other tissues and fluids, some of which are present only in very small or trace amounts. The term “trace elements” was applied by nutritionists and biochemists to those elements that are present in very small amounts, relative to the major constituents of tissues, and that are required for proper growth and development.1 The central nervous system (CNS), particularly the limbic system, is the main site of storage of iron (Fe), zinc (Zn), copper (Cu), and selenium (Se). The limbic system is a set of brain structures that form the inner border of the cortex and support a variety of functions related to motor coordination, emotions, behavior, memory, and olfaction.

During early development, especially the gestational period and the first year of life, the limbic system is more vulnerable to all types of disruptions than it is later in development.2 Specific information about excesses and deficiencies of trace elements during early development is limited. The elements iron, zinc, copper, and selenium perform structural and catalytic functions in proteins and enzymes involved in structural, metabolic, and antioxidant functions3 and also participate in the synthesis of neurotransmitters, specifically catecholamines. The catecholamines dopamine (DA) and norepinephrine (NE) are neurotransmitters synthesized from the amino acid tyrosine, formed by a catechol group and an amino group.4 Dopamine regulates feelings of well-being and reward,5 social interaction,6 control of voluntary movements,7 and learning.8 NE modulates high motivational salience,9 food-related motivational behavior,10 memory,11 and brain development.12

Humans and animals with imbalances of iron, zinc, copper, and selenium show behavioral changes such as attention and memory deficits, anxiety, and depression. In old age, excesses of these trace elements combined with enhanced oxidative processes promote the development of Lewy bodies,1315 amyloid β plaque,1618 and defects in the huntingtin gene15,19; these processes are associated with the neurodegenerative pathologies of Parkinson's,16 Alzheimer's,20 and Huntington's21 diseases, respectively.

Excesses and deficiencies of iron, zinc, copper, and selenium have not received adequate study or attention, despite their importance in emotional, cognitive, and neurodegenerative processes. Some diseases associated with changes in the brain caused by iron, zinc, copper, or selenium imbalance are highly prevalent worldwide; one example is depression, which affects more than 21% of the world's population and is considered a major public health problem.22 The mean prevalence of Parkinson's disease in the United States in individuals aged 65–69 years is 2,950 per 100,000.23 Alzheimer's disease is the most common neurodegenerative disorder in elderly individuals, affecting more than 24 million people worldwide. Moreover, over 5 million new cases of Alzheimer's disease are reported each year.24 For this reason, this review summarizes the evidence suggesting the involvement of the trace elements iron, zinc, copper, and selenium in different pathologies of the limbic system, examining deficiencies or excesses that induce brain metal imbalance.

LIMBIC SYSTEM

The term “limbic” has its origins in the Latin word limbus, which means border or frontier.25 It was first used by Pierre Paul Broca in 1878 to identify the cortical structures forming the inner border of the cortex, including the cingulate and parahippocampal gyri. In 1937, the physiologist James Papez proposed that this area constitutes a neuronal circuit that controls emotional experiences or subjective feelings and behaviors. This anatomical model is now referred to as the Papez circuit, the circuit of emotions, or the emotions center.25,26 In 1948, Yakovlev proposed an alternative emotion-controlling circuit, formed by the orbitofrontal, the insular, and the anterior temporal lobe cortices, the amygdala, and the dorsomedial nucleus of the thalamus.27 In 1952, Paul D. MacLean used the term “limbic system” to describe subcortical structures such as the hypothalamus, the septal area, the amygdala, and the nucleus accumbens, as well as cortical areas such as the orbitofrontal cortex.25 More information about the history of the limbic system can be found in previous reviews.2527

STRUCTURES AND FUNCTIONS OF THE LIMBIC SYSTEM

The brain structures that form the limbic system and perform its functions have been the subject of several literature reviews,25,26 which are briefly summarized here. The main structures forming the limbic system (Figure 1) are divided into two regions: the cortical regions, including the parahippocampal and cingulate gyri, the prefrontal cortex, and the orbitofrontal cortex; and the subcortical regions, comprising the hippocampus, the amygdaline nucleus, the septal nucleus, the nucleus accumbens, the striatum, the mammillary bodies, the hypothalamus, the thalamus, the ventral tegmental area, the raphe nucleus, the locus coeruleus, and the substantia nigra.28,29Table 1 presents the main functions of the limbic system structures, based on several literature reviews.2634

Figure 1

Limbic system pathways. The mesolimbic pathway innervates the ventral tegmental area, the striatum, the amygdala, and the nucleus accumbens2936; the mesocortical pathway projects from the ventral tegmental area towards the prefrontal cortex3236; the nigrostriatal pathway projects from the substantia nigra to the striatum3436; and the tuberoinfundibular pathway projects from the hypothalamus to the pituitary.3036

View this table:
Table 1

Main functions of limbic system structures.

Limbic area or structureFunction
Amygdaline nucleusModulates attention, mood, emotional memory, emotional expression, fear, reward, novelty, positive expectations, anxiety, aggression, social cognition, selection of food
Parahippocampal gyrusSpatial memory
Cingulate gyrusMood, emotional experience, memory, generation and regulation of emotions, emotional resolution of conflicts, modulation of pain sensation
Autonomic functions: blood pressure, cardiac output
HippocampusLong-term memory, learning, emotional experience
Prefrontal cortexDecision taking, integrative and cognitive functions
Orbitofrontal cortexAssessment of reward or punishment stimuli
Nucleus accumbensModulates motivation and reward, addictions
StriatumReward and punishment, motivation, addictions
Mammillary bodiesMemory
Ventral tegmental areaModulation of motivation and reward
ThalamusProcessing of emotional information. Includes motor and behavioral components of emotional responses
HypothalamusNeuroendocrine control, emotional expression. Regulation of the autonomous nervous system: control of blood pressure, cardiac output, hunger, satiety, sexual behavior, circadian rhythms
Substantia nigraMotor coordination
  • Data derived from previously published studies and reviews.233

The limbic system is subdivided into pathways or tracts that follow its principal neuronal projections (Figure 2). The mesolimbic pathway projects from the ventral tegmental area and innervates the nucleus accumbens, the striatum, and the amygdala; this pathway is associated with emotion and reward processes.2936 The mesocortical pathway also projects from the ventral tegmental area, originating at the A10 nucleus of dopaminergic neurons (i.e., towards the prefrontal cortex and the medial cingulate gyrus); this pathway is also associated with reward processing.3236 The projecting axons of the nigrostriatal pathway originate in the A9 nucleus of dopaminergic neurons, located in the substantia nigra and ending at the striatum; this projection is strongly related to motor control.3436 Finally, the tuberoinfundibular pathway is a set of projections originating in the arcuate and paraventricular nuclei of the hypothalamus; this pathway innervates the pituitary gland and is associated with neuroendocrine regulatory functions (Figure 1).3036

Figure 2

Distribution of trace elements in the limbic system. Iron is more concentrated in the basal ganglia, specifically in the substantia nigra, putamen, the caudate nucleus, and the globus pallidus.62,63 The hippocampus shows the highest concentrations of zinc (Zn),43 copper (Cu),24,25 and selenium (Se).137

OVERALL IMPORTANCE OF TRACE ELEMENTS

Iron

The trace element iron is obtained from dietary sources. Physiologically, iron is continuously recycled within the body because there is no specific route of excretion. As a transition metal, iron has the capacity to accept or donate electrons, and it acts as either an oxidizing or reducing agent in a large number of biochemical reactions.37 A high proportion (65%) of this element is incorporated into the heme group of hemoglobin molecules, while the remainder is bound to other heme and nonheme (sulfur–iron) proteins where it participates as a cofactor in multiple enzymatic reactions. Of particular importance in relation to the limbic system is its incorporation into enzymes such as tyrosine hydroxylase, the rate-limiting enzyme in the synthesis of catecholamines, and other mono-oxygenase enzymes, such as phenylalanine hydroxylase and tryptophan hydroxylase, which catalyze, respectively, the conversion of phenylalanine to tyrosine and tryptophan to 5-hydroxytryptophan (precursors of catecholamines and serotonin, respectively). The element iron is also essential for the activities of monoamine oxidase enzymes, which catalyze the degradation of biogenic amines. Many other iron-bound enzymes participate in important metabolic activities, including the Krebs cycle, the mitochondrial respiratory chain,38 and the synthesis of lipids and DNA.32,39 Magnetic resonance imaging shows that iron distributions in the CNS are closely correlated with the anatomical distribution of white matter; this confirms studies indicating that oligodendrocytes are the main cellular repository of cerebral iron.39 In central neurons, iron is principally located within the cytosolic space and in the dendrites of dopaminergic neurons. In limbic areas, DA and iron are co-localized in storage vesicles.40

Zinc

After iron, zinc is the most abundant metal present in the CNS. The element is involved in the activities of approximately 300 enzymes, some of which are crucial for DNA and mRNA synthesis.41 For instance, zinc is a cofactor of DNA and RNA polymerases and endonucleases, and it participates in the stabilization of DNA and chromatin structures.41,42 Bound to metalloenzymes, zinc participates as a prosthetic group in multiple catalytic, regulatory, and structural stabilizing activities.41 Zinc markedly enhances the affinity of human growth hormone for the extracellular binding domain of the human prolactin receptor.43 Zinc is the most abundant trace metal in the brain and is most heavily concentrated in the hippocampus. It has been determined that, during neurotransmission involving glutamatergic neurons, zinc and glutamate are co-released into the synaptic cleft.44 The released zinc ions act upon N-methyl-D-aspartate (NMDA), α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA), and gamma-aminobutyric acid (GABA) A receptors, which reduce the activity of GABA transporter 4.4146

Copper

Copper is a potentially toxic element due to its chemical redox potential and its ability to participate in free radical reactions, which may be harmful to cellular functions and structures.47 Similarly to iron, copper allows the transference of electrons in key oxidative processes, as exemplified by its role in the electron transport chain,48 where it is linked to cytochrome c oxidase, a large metalloenzyme expressing two heme and two copper reaction centers; thus, copper plays a central role in respiration. The element also plays an important role in buffering oxidative stress by reducing the potential harmful presence of oxygen radicals in cytosol; here, it is associated with the activities of copper/zinc-dependent superoxide dismutase.49 Copper is also linked to enzymes important in CNS neurotransmission, such as DA-β-hydroxylase,50 the only membrane-bound enzyme involved in neurotransmitter synthesis and capable of producing NE directly inside of vesicular membrane structures.11 A variety of enzymes contain copper in their prosthetic groups4752; these include tyrosinase, which is responsible for the synthesis of melanin53; lysine oxidase, which internally cross-links collagen and also elastin50; peptidyl glycine α-amidating mono-oxygenase, a metalloenzyme that synthesizes neuropeptides52; and ceruloplasmin, which participates in iron homeostasis.54

Selenium

The overall importance of selenium, in contrast to copper, iron, and zinc, is that this metal acts as a cofactor of antioxidant enzymes, such as glutathione peroxidase, a protein that protects against free radicals.55 Other selenium-bound proteins, such as thioredoxin reductase, reduce other proteins by using nicotinamide adenine dinucleotide phosphate as a reducing agent, thereby producing thiol groups in sites where disulfide bridges are present.56 Iodothyronine deiodinases constitute a family of selenoenzymes that selectively remove iodide from thyroxine and its derivatives, thus activating or inactivating these hormones.57 In the CNS, the selenoenzymes have an important redox function that can reduce neuronal cell death.58,59

DISTRIBUTION AND TRANSPORT OF TRACE ELEMENTS IN THE CENTRAL NERVOUS SYSTEM

Iron distribution and transport

Iron alternates between its ferric (Fe3+) and ferrous (Fe2+) states, depending on metabolic and physiological needs.60 Iron is transported in its Fe3+ form across the blood-brain barrier while bound to transferrin (Tf), a glycoprotein responsible for the systemic transport and distribution of Fe3+ within tissues.39 In the CNS, the iron-Tf complex is internalized within cells, owing to a transport mechanism performed by the transferrin type 1 receptor (TfR1); the transferrin type 2 receptor (TfR2), on the other hand, is not highly expressed in this tissue.39 Both the TfR1 and TfR2 receptors are transmembrane glycoproteins expressed on cell surfaces in almost all tissues, with the strongest expressions occurring in liver, bone marrow, and endothelial cells of the blood-brain barrier capillaries.61 Another route of iron absorption into the CNS is through the choroid plexus. The expression of a number of compounds important for iron transport has been determined in the choroid plexus by using in situ hybridization and immunocytochemistry; these include Tf, transferrin receptor (TfR), divalent metal transporter 1, ceruloplasmin, and ferroportin.61

The binding of iron and Tf/TfR1 allows the subsequent formation of an endosome that transports the iron-Tf/TfR1 complex intracellularly through cerebral capillaries. The iron-Tf/TfR1 complex is then exposed to the interstitial CNS microenvironment between the capillaries and the astrocyte endfeet. Here, iron is released and then immediately recaptured by Tf, citrate, or ascorbate.39 Once the metal has been captured, it enters diverse metabolic pathways in neurons and glial cells, including the microglia.39,61 The cerebral regions exhibiting the highest iron content in adults are the globus pallidus, the putamen, the dentate gyrus, and the substantia nigra,62,63 which form parts of the dopaminergic mesolimbic system (Figure 2); this distribution indicates the importance of iron in the dopaminergic mesolimbic system. High-resolution images, such as synchrotron X-ray chemical nanoimaging, show iron deposits in cytosolic compartments and in the dendrites of dopaminergic neurons; importantly, iron and DA were observed to be co-localized in dopaminergic secretory vesicles.40

Zinc distribution and transport

The highest absorption rates of Zn2+ are observed in the jejunum, the middle section of the small intestine connecting the duodenum and the ileum. In this organ, the transport of zinc is energy dependent. Following absorption in the jejunum, zinc is systemically transported by albumin, Tf, alpha-2-macroglobulin, and immunoglobulin G and, once captured in the bloodstream, is distributed to diverse tissues.43 In the CNS, zinc transporter (ZnT) 3, which is localized in neuronal membranes, captures zinc and stores it in cytosolic vesicles.3 In the brain, zinc-containing neurons are localized in the olfactory bulb,64,65 the cortex, the cerebellum, and the limbic system.66 Within the limbic system, areas such as the hippocampus, the subicular area, the retrosplenial region, the cingulate cortex, and the anterodorsal thalamic nucleus show the highest levels of zinc.41,67

The concentration of zinc in cerebrospinal fluid is about 10 µg/L, which is similar to concentrations observed in blood serum. The global brain content of zinc is approximately 13–17 µg/g tissue, with concentrations in white matter lower than those in grey matter. The zinc concentration in grey matter is approximately 50–80 µg/g. The hippocampus is rich in zinc, specifically in the mossy fibers that project from the granule cell layer of the dentate gyrus to the pyramidal cells of region CA343 (Figure 2). It is estimated that 85–90% of zinc is bound to enzymatic complexes, the cytoskeletal proteins, the extracellular matrix proteins, and the metallothioneins, a family of low-molecular-weight proteins that are rich in cysteine residues and that also bind copper and selenium through thiol groups; metallothionein III is conspicuously expressed in the CNS. The remaining 10–15% of zinc occurs in its ionic form stored in synaptic vesicles. The neurons in neurotransmitter secretory vesicles showing the highest contents of zinc are the glutamatergic and the “zinc-rich” neurons.41 Regarding the intracellular distribution of zinc, 30–40% is localized in the nucleus and 50% is localized in the cytoplasm and associated structures.41

In the CNS, zinc plays a significant role in neurotransmission processes, in addition to performing general functions as components of metalloenzymes and as structural elements of molecules such as DNA and RNA.43 In approximately 50% of glutamatergic neurons, zinc is found in presynaptic vesicles at concentrations of 1 mmol/L; it is released jointly with glutamate.6871 Synaptic vesicles capture zinc using transporter ZnT3.72 Similarly, zinc permeability takes place through several types of Ca2+ channels, including the NMDA receptor channel, voltage-dependent Ca2+ channels, and the AMPA/kainate receptor channel.18 Postsynaptically, zinc enters neurons mainly through L-type voltage-dependent Ca2+ channels and glutamate NMDA receptor channels during the depolarization phase, where it acts as a neuromodulator.70,73 Once internalized, zinc is stored and later modulates the functions of zinc-dependent proteins.18 Excess zinc in the cytoplasm activates ZnT1 membrane transporters, which extrude it to the extracellular environment. On the other hand, ZnT2 binds and transports zinc into cellular compartments, and ZnT3 translocates zinc to the interior of synaptic vesicles. This overall process of cellular capture, storage, and extrusion, however, is not entirely understood.41 Zinc is ubiquitously localized in dopaminergic neurons, with slightly higher concentrations in the nuclei; no selective accumulation of this metal has been observed in neurotransmitter vesicles, as observed with iron.40 As a modulator of neural transmission, zinc inhibits activities in a manner similar to that of glutamate decarboxylase, an enzyme involved in the synthesis of GABA. In this way, zinc regulates neuronal excitability by reducing the synthesis of GABA and blocking its receptors.43

Copper distribution and transport

The transport of Cu2+ requires the participation of P-type ATPase transporters, namely ATPase 7A (ATP7A) and ATPase7B (ATP7B), enzymes that are critical in copper homeostasis.74 Other transporters participating in copper homeostasis include those that control its cellular capture, including copper transporter 1; copper transporter 1 represents the main route of cellular copper into mammals, a consequence of its high affinity for copper; copper transporter 2 exhibits less affinity for copper. The copper transporter 1 molecule is homogeneously expressed within the CNS, mainly in the choroid plexus; its lack of expression is fatal, leading to embryonic death.4775

Other transporters that control copper fluxes are dependent on ATP7A and ATP7B; the latter, which is expressed in the brain, utilizes metabolic energy for copper transport. Among the copper transporters and chaperones, which release the metal to specific proteins like cytochrome C oxidase and superoxide dismutase, are antioxidant protein 1, cytochrome C assembly proteins 11 (COX11), COX17, COX19, COX23, copper chaperone for superoxide dismutase, and synthesis cytochrome oxidase 1 and 2.4776 Inactivation of these transporters in the cell could lead to a reduction in the copper flux, with consequent cellular overload or alteration of the physiological processes in which it participates, such as mitochondrial oxidative respiration.49,51

Selenium distribution and transport

The transport mechanisms of selenium into brain tissue have not been completely elucidated; nevertheless, it has been proposed that the transport mechanisms are similar to those of ionic iron. Selenoprotein P, a glycoprotein synthesized in liver, is the main selenium transporter, incorporating 10–12 atoms per molecule using coordination bonds formed with cysteine. Up to 60% of the selenium circulating in plasma is bound to selenoprotein P. The brain and other organs absorb selenium from selenoprotein P, with lesser amounts absorbed from other selenium-binding proteins, such as glutathione peroxidase.7779 At the blood-brain barrier, selenoprotein P binds to the apolipoprotein receptor, which belongs to a family of low-density lipoprotein receptors that are expressed predominantly in the brain; the apolipoprotein receptor regulates neuronal migration, cortical lamination, synaptic function, and, importantly, selenium absorption.78,80 Once selenoprotein P binds to its receptor, the apolipoprotein receptor–selenoprotein P complex is endocytosed and selenium is released from selenoprotein P through the action of selenocysteine lyase; selenium is thus released into the interstitial space, where it is captured by other circulating selenoprotein molecules for further neuronal use, and selenoprotein P is recycled.81,82

DEFICIENCY OR EXCESSES OF TRACE ELEMENTS ASSOCIATED WITH DIVERSE LIMBIC SYSTEM PATHOLOGIES

Iron deficiency

Gestation, childhood, and early adolescence are stages of life representing the highest risks of iron deficiency. The child is particularly vulnerable in and around the perinatal period, owing to maternal conditions such as smoking, hypertension, and diabetes mellitus, the most common causes of maternal iron deficiency.83 Diabetes mellitus is particularly prevalent throughout the world. It is estimated that 30–50% of pregnant women show some degree of iron deficiency,84 resulting not only from inadequate diets (in terms of the quality or quantity of the iron content) but also from absorption alterations, excessive zinc intake, and other causes.43 Because neuronal development is especially important during gestation and infanthood, the impact of iron deficiency on developmental processes is potentially severe, leading to functional, morphological, neurochemical, and bioenergetic alterations. Taken as a whole, the negative impacts of iron deficiency on developmental processes can persist for the duration of an afflicted person's life, depending on the timing of onset and the duration and severity of the deficiency.

Limbic system pathologies associated with iron deficiency

Hippocampal alterations.  The hippocampus is involved in spatial memory and recognition as well as cognitive functions. It is one of the structures most affected by iron deficiency, thus explaining why this condition is associated with memory impairments.8486 It has been observed that iron deficiency changes the morphology of the hippocampus, diminishing the extent of dendritic branching and the numbers of neuronal interconnections. This condition has serious repercussions for attention and memory, specifically for recognition memory.87

An increased risk of developing iron deficiency has been observed in children of diabetic mothers. Studies have assessed the cortical auditory response and auditory recognition memory of iron-deficient children in response to the voices of their mothers as compared with the voices of unfamiliar people; electrophysiologically, the evoked-related potentials of iron-deficient children (ferritin < 34 µg/L) showed altered recognition of their mothers' voices, as well as delayed motor development.88 The children who had chronic iron deficiency early in life, although provided with supplemental iron later in life, did not achieve optimal scores on cognitive tests, as compared with normal iron-replete children.89,90

Alterations of hippocampal function have been observed in a murine model of dietary iron deficiency. Iron-deficient rats show delays in learning acquisition processes that depend on the hippocampus.85 It has also been documented, in rats, that prenatal iron deficiency alters the activity of cytochrome C oxidase, leading to a reduced rate of oxidative phosphorylation, particularly in the hippocampus and prefrontal cortex. A similar but lesser reduction is also observed in the striatum and the amygdala.87

The hippocampus is severely affected by ischemia and hypoxia, and, subsequent to perinatal iron deficiency, the susceptibility of the rat hippocampus to hypoxic-ischemic damage increases.91 In addition, iron deficiency increases the severity of cerebral edema in the event of brain hemorrhage and delays recovery from such injuries, probably due to delayed tissue regeneration and/or an increase of Tf and TfR expression in the zones adjacent and peripheral to the hemorrhage, thus promoting oxidative damage related to increased iron transport.92

Myelination.  Oligodendrocytes are particularly sensitive to iron deficiency.93,94 Decreased ingestion of iron and alterations of iron-storage capacities both lead to a reduction in the synthesis of myelin proteins and lipids, resulting in reduced wrapping and compaction of myelin around axons.93 Behaviorally, the effects of iron deficiency are patently manifested, even after rectification of the deficiency.95

Neurotransmitter synthesis.  The predominant neurotransmitter in the limbic system is DA, and its synthesis depends on the integrity of the tyrosine hydroxylase enzyme. This enzyme uses iron as a cofactor; thus, iron deficiency causes a reduction in the synthesis of catecholamines.94 Reductions in the synthesis, concentration, and release of neurotransmitters cause serious motor, learning, and memory alterations as well as other changes. Besides causing a decrease in DA levels, it has also been reported that iron deficiency causes a reduction in levels of DA receptors in mesolimbic areas, especially in the accumbens, the caudate-putamen nucleus, and the prefrontal cortex.85 Reductions of dopaminergic activity in the limbic system have been related to reduced motor activity, increased anxiety, and deficient exploration of new environments.85

Depression.  Depression is a mental condition characterized by symptoms of increased unhappiness, anhedonia, irritability, concentration difficulties, loss of appetite, and sleep alterations.96 Limbic structures are implicated in the etiology of depression because these structures control and regulate emotions. Activities of the amygdala and the cingulate cortex are chronically elevated in individuals afflicted by depression. On the other hand, stimulation of the accumbens nucleus and the striatum leads to a reduction in symptoms, resulting in the modulation of gratification and reward processes.96 These areas are innervated by neuronal projections that release the monoamines DA, serotonin, and NE; depression has been linked to a reduction in the levels of these neurotransmitters. Iron deficiency has been linked to alterations in the regulation of DA synthesis as well as to a reduction in the expression and density of iron receptors and transporters.94 Iron deficiency, either associated or not associated with anemia, alters social and emotional behavior, resulting in increased introversion, lessened affection, increased anxiety, and depression.89 These behavioral alterations can be reversed in a dose-dependent manner by iron supplementation. Other researchers have observed altered mother–child interactions directly related to the severity of iron deficiency.97

Schizophrenia.  According to Sorensen et al.,98 who followed a cohort of nearly 1.2 million Danes, the children of mothers diagnosed as anemic while pregnant were 1.6 times more likely to show symptoms of schizophrenia than children born to mothers who were nonanemic during pregnancy. Schizophrenia is accompanied by a reduction in the volume of the limbic system, associated with the size of Papez circuit. Reductions in the size of the hippocampus and diminishment in the numbers of GABAergic neurons in the cingulate cortex and anterior thalamus result in glutamatergic excitotoxicity.26

Attention deficit hyperactivity disorder.  Attention deficit hyperactivity disorder (ADHD) is a psychiatric disorder usually diagnosed in childhood and characterized by an inappropriate lack of attention, motor hyperactivity, and impulsivity. Perinatal environmental factors play a significant role in the etiology of this disease. Iron deficiency is one of the factors that have been linked to ADHD pathogenesis.99 The degree of iron deficiency, as determined by expression levels of ferritin, has been correlated with the severity of ADHD symptoms.100 Iron deficiency leads to dopaminergic dysfunction, which is a common manifestation of this syndrome. As already mentioned, alterations in the release of DA and the density of its receptors result from deficiency of iron.94,100 Dopaminergic alterations are related to modifications of limbic structures, especially reductions in the sizes of the prefrontal and cingulate cortices, the nucleus accumbens, the putamen, the corpus callosum, and the hippocampus.99,101 Modifications of the amygdala and the orbitofrontal cortex resulting in uninhibited behaviors are a characteristic feature of ADHD26,101; modified nigrostriatal projections have also been observed.102 The manifestations of altered control are observed in components of cognitive and attentional functions such as alertness, orientation, cognitive flexibility, continued attention, response inhibition, and working memory; other altered affective components include motivation and aversion. Motor alterations associated with ADHD include structural and functional abnormalities of the cerebellum and the basal ganglia.99 Using iron supplementation, it is possible to improve the symptoms of ADHD in children previously diagnosed as anemic.100

Iron excess

Free iron has a strong potential to form free radicals (including reactive oxygen species), molecules that contain one or more nonpaired electrons.103 It acts as a pro-oxidant, catalyzing the formation of hydroxyl radicals through the Fenton reaction,13 by which Fe2+ participates as an electron donor in favor of hydrogen peroxide and turning into Fe3+, OH-, and the free radical OH.104 The presence of free iron has also been associated with lipid peroxidation, protein oxidation, and neuronal damage,16 after which cognitive and motor alterations are evident.104

Limbic system pathologies associated with iron excess

Friedreich's ataxia.  Friedreich's ataxia is a recessive autosomal degenerative disease characterized by the development of muscle weakness. It is caused by a mutation in the frataxin gene, located on chromosome 9q13. Frataxin is a mitochondrial protein that plays an important role in iron homeostasis.105 For instance, complex I in the electron transport chain possesses eight iron-sulfur complexes, and an imbalance in the regulatory genes leads to iron accumulation in the mitochondria, which increases the probability of free radical formation and cell death.106 The accumulation of iron in brain tissue, particularly in the substantia nigra and the globus pallidus,107 leads to dystonia, a pathology characterized by sustained muscle contraction, body twists, repetitive movements, and abnormal postures. Afflicted patients also show signs of speech disorders and psychiatric manifestations.104 It has been reported that Friedreich's ataxia and schizophrenia may be related,108 suggesting that iron accumulation might affect multiple limbic areas and neurotransmission systems.

Parkinson's disease.  Parkinson's disease is a condition resulting from severe damage of the nigrostriatal pathway after loss of dopaminergic neurons. The striatum intervenes in the initiation and control of movements, modulating cortical descending pathways.35 Dopaminergic neuronal cell death results in the characteristic symptoms of the disease,109 including difficulties in the initiation and termination of movements, bodily tremors at rest, bradykinesia, postural rigidity, and instability.15 The formation of Lewy body deposits of α-synuclein at neuronal ends is a characteristic feature of Parkinson's disease105; the Lewy body deposits interfere with synaptic integrity.109 Postmortem studies of the brains of human Parkinson's disease patients show an increased iron content in the basal ganglia, particularly in the substantia nigra14,104; the elevated iron content can range from 25% to 100% above average levels.104 Iron excess in the substantia nigra leads not only to deposition of Lewy bodies but is also a high risk factor for oxidative damage to dopaminergic neurons forming the nigrostriatal pathway.110 Neuronal damage also plays an important role in cognitive alterations and depression observed in parkinsonian patients.109 In experimental animal models, iron chelation therapy ameliorates the symptoms of parkinsonism.104 In the well-known murine model of the disease, in which injury to either the substantia nigra or the nigrostriatal pathway is caused by 6-hydroxydopamine,104 periventricular administration of the iron chelator deferoxamine is effective in protecting the striatum as well as in supporting behavioral recovery.20

Alzheimer's disease.  The pathological evidence of Alzheimer's disease is the formation of plaques or tangles of regularly deposited fibers, i.e., spherical structures deposited in interstitial spaces where the main component is amyloid β (Aβ) peptide. These filamentous deposits result from the proteolytic degradation of the Aβ precursor protein and lead to axonal and cholinergic neuron damage. The limbic functions of these types of neurons are compromised, with an associated loss of choline acetyltransferase and acetylcholinesterase enzymatic activity.17 The Aβ peptide has a strong affinity for metals showing binding sites for Fe3+, which leads to the precipitation of this peptide and an increased resistance to proteolysis. It has been observed that metal homeostasis is altered in Alzheimer's patients, with increased iron levels being up to 3–5 times those observed in healthy individuals of the same age.105 Cerebrospinal fluid obtained from Alzheimer's patients shows increased mean iron levels of up to 9.94 µmol/L (range 0.5–31.7 µmol/L).111

Zinc deficiency

Zinc deficiency is a highly prevalent pathology; in the last decade, 4 million people were chronically afflicted in the United States.43 Zinc deficiency led to loss of taste and olfaction, alopecia, dermatitis, diarrhea, reduced immune response,43 increased neuronal apoptosis,112 and decreased learning ability in animal models.113,114 In addition, vesicular zinc in the hippocampus modulates neuronal survival and neurogenesis.115

Deficiency results when zinc requirements are not met, due to either inadequate consumption of zinc-containing nutrients or absorption difficulties after ingestion of zinc. Absorption difficulties are caused by phytate-containing foods, by excessive copper or Fe2+ ingestion, or by diminished absorption capabilities in elderly people.43

Limbic system pathologies associated with zinc deficiency

Studies performed in rodents show that zinc deficiency during critical stages of development leads to delayed bodily growth, delayed CNS maturation, and, to a lesser degree, reduced brain size, thus affecting behavior and memory,43 although the changes in brain size have not been fully elucidated.

Zinc excess

Zinc accumulation in the CNS causes neuronal and glial toxicity. It has been observed that excess zinc leads to organelle destruction, DNA fragmentation, and increased activity of caspases after activation of p75 and preapoptosis proteins like cytochrome C and apoptosis-inducing factor. Increasing the extracellular concentration of zinc in vitro results in neurotoxicity; cell death occurs in cortical neurons exposed to zinc concentrations ranging from 250 µM to 1,000 µM for periods of 15 minutes up to 24 hours.116,117 Cerebral ischemia increases the activity of zinc-containing enzymes, which is conducive to increased accumulations of the metal in the neuronal soma, ending in cell death; this can be reversed by administration of zinc chelators (N-6-methoxi-8-quinolyl-para-toluenesulfonamide).18 It has also been observed that zinc accumulation leads to cell death by oxidative stress, as confirmed by determining the expression of oxidative damage markers, i.e., superoxides and lipoperoxidases.118,119

Limbic system pathologies associated with zinc excess

Epilepsy.  After convulsive epileptic episodes, abnormally elevated concentrations of zinc have been observed in hippocampal interneurons, particularly in those of region CA3. During an epileptic episode, neuronal Ca2+ increases, causing excessive release of zinc from mitochondrial stores and extracellular accumulation. Because zinc inhibits NMDA and GABA A receptors, the excitability of hippocampal circuits is blocked, thus contributing to the development of seizures. Likewise, high concentrations of zinc result in mitochondrial dysfunction, causing neuronal cell death.46,72 Intraventricular injection of zinc initiated convulsions in rats,43 during which mossy fibers showed an increment of released zinc. The zinc, in turn, inhibited the release of GABA, increasing excitability and, concomitantly, the convulsive episode.18,120

Alzheimer's disease.  Increases in the brain concentrations of zinc, copper, and iron cause interactions of these trace elements with the Aβ plaque, contributing to the accumulation of the peptide and thus to its neurotoxicity. Under normal conditions, zinc participates as a cofactor of metalloproteinases such as neprilysin, the enzyme responsible for insulin lysis. Zinc-dependent enzymes degrade the Aβ plaque, thus preventing its intercellular accumulation. Under pathological conditions, as in Alzheimer's disease, the homeostasis of zinc and other trace elements such as copper and iron is altered.111 Intercellular free zinc promotes the deposition of Aβ plaque by binding to histidine 13, a process that plays a critical role in the aggregation of plaque and the extension of its half-life. Thus, the whole process of aggregation confers resistance to proteolytic degradation to the Aβ plaque. Nevertheless, this effect appears to be reversed by administration of zinc chelators.18 It has been reported that up to 1 mM of zinc accumulates in Aβ plaques.

According to Strozyk et al.,111 increased zinc concentrations in cerebrospinal fluid were observed in human autopsy samples of individuals with Alzheimer's disease; this association, however, is controversial. Ritchie et al.,121 after performing a pilot study supplying clioquinol (iodochlorhydroxyquin), a zinc and copper chelator, to patients with moderate Alzheimer's disease, observed a reduction in plasmatic Aβ peptide that correlated with the formation of cerebral Aβ deposits; however, the clioquinol showed a marked benefit only in severely afflicted patients.121

Microglial activation.  Microglial cells are considered CNS resident macrophages; they acquire an amoeboid shape when migrating to lesion sites, where they release metalloproteinases, reactive oxygen species, and cytokines. Extracellular zinc can perform as a direct activator of microglia, as has been observed after administration of 15–60 mM ZnCl2. This effect was corroborated in situ after inoculation of the same solution directly into the hippocampus; i.e., the activation of microglia and the attainment of an amoeboid shape paralleled the increase in cytokine expression.68

Zinc is released from both synaptic vesicles and protein-binding sites during ischemia-reperfusion injury.68 These studies suggest that endogenous zinc release is an early signal that triggers microglial activation after ischemia.122 Microglia account for 15% of CNS cells, and their participation in the neuroinflammatory response is critical. However, on its own, sustained microglial activation leads to dysregulation of the inflammatory response.123 Neuroinflammatory processes and the consequent increase of zinc levels in limbic areas such as the hippocampus are considered a critical component in the etiology of Alzheimer's and Parkinson's diseases,124 both of which are associated with limbic areas such as the hippocampus on account of their high Zn contents.71

Copper deficiency

In humans, copper deficiency is an uncommon pathology that can originate from gastric surgery, malabsorption diseases, or excessive zinc or iron consumption. Excessive zinc consumption leads to increased synthesis of metalloenzymes in the intestinal mucosa; these enzymes have a high affinity for copper and inhibit its absorption.50 In experimental murine models, a copper-deficient diet results in up to a 74% reduction in the cerebral copper content. When the dietary availability of copper is low, the brain responds with compensatory mechanisms to increase the expression of Crt1 receptors in the choroid plexus, which increases copper uptake into the brain.75 Copper deficiency reduces the activity of enzymes in which it participates as a prosthetic group49; cytochrome oxidase, a metalloenzyme participating in oxidative phosphorylation, provides an example of this. Other alterations related to copper deficiency are anemia, neutropenia, and the reduction in the catalytic activity of enzymes employing copper as a cofactor during cell proliferation and differentiation in bone marrow.50

Limbic system pathologies associated with copper deficiency

Neurological manifestations.  The most common neurological alterations associated with copper deficiency are myelopathy with spastic gait and sensorial ataxia; CNS demyelination, optical neuritis, and isolated peripheral neuropathy have also been reported.50 Copper is linked to important enzymes related to CNS neurotransmission, such as DA-β-hydroxylase4,50; this enzyme requires two units of copper per unit of DA-β-hydroxylase for optimal activity.125 In the limbic system, the failure of ATP7B activity alters the influx of copper126; this affects the activity of DA β-hydroxylase, resulting in lower NE and higher DA concentrations.126128 NE performs important functions by regulating responses to stress and by participating in memory, impulse control,129 and attention functions,130 all of which could be affected by reductions in neurotransmitter levels. Alterations in NE levels have also been correlated with ADHD131 and Alzheimer's132 and Parkinson's15 diseases; thus, copper deficiency merits further analysis and study as a possible component of these diseases.

Menkes disease.  Menkes disease is the result of a congenital copper deficiency resulting from mutations in the ATP7A gene, located on chromosome Xq12-q13. Loss of function of this protein results in failed copper transport across the gastrointestinal tract membrane, the placenta, and the blood-brain barrier, thus increasing the concentration of the metal in the cells of the duodenum mucosa. Patients with this disease show developmental delays, mental retardation, seizures, altered body temperature control, grey matter degeneration, Purkinje cell abnormalities, and neuronal loss in the hippocampus. All of these manifestations have been associated with deficiency in the catalytic activity of copper-dependent enzymes.49133

Copper excess

Although excessive consumption of copper is an uncommon pathology, there are disorders in the expression of copper transporters that favor abnormal copper accumulations. Because copper plays an important role in redox reactions, the metal could be a source of reactive oxygen species, which are extremely toxic to cells.

Limbic system pathologies associated with copper excess

Wilson's disease.  Wilson's disease is an autosomal recessive pathology in which the transporter protein ATP7B is not activated, thus compromising the adequate excretion of biliary copper. For this reason, copper becomes unusually accumulated in the liver and in other tissues, including the CNS, where it triggers neurological disorders. Copper chelators are useful in reducing the damage caused by excess copper.47,49 Wilson's disease results in comprised neurodegenerative processes in the basal ganglia, parkinsonian manifestations, and neuropsychiatric disorders.133

Huntington's disease.  Huntington's disease is a neurodegenerative pathology characterized by motor decline, bradykinesia, dystonia, rigidity, and cognitive and psychiatric impairments. The psychiatric impairments are observed in conjunction with symptoms of depression, apathy, obsessive-compulsive disorders, and psychosis.21 Neuronal cell death is present in areas such as the striatum and the cerebral cortex, which corresponds to the expansion of glutamine domains at the NH2 end of huntingtin. This situation leads to aberrant interactions of this protein with proteins such as transcription factors and caspases.19 Oxidative damage is also a feature of Huntington's disease, promoting mitochondrial dysfunction, particularly in limbic regions.134,135 Postmortem examinations of brains from humans with Huntington's disease show increased concentrations of copper, mainly in the putamen and the substantia nigra.14 It appears that increased concentrations of copper in these areas promote the progression of the disease through interactions of huntingtin with pro-oxidant agents.135

Selenium deficiency

It is estimated that approximately 1 billion people worldwide suffer from selenium deficiency.136 Selenium concentrations in the brain are not high; however, in contrast to most other organs, the brain remains remarkably stable during selenium deficiency, most likely at the expense of other organs.137 Brain tissues capture selenium using selenoprotein P, thus keeping the activity of brain glutathione peroxidase at an optimal level, even under conditions of selenium deficiency. Thus, long-term insufficient ingestion of this element could have deleterious effects on the CNS.77136

Limbic system pathologies associated with selenium deficiency

Alterations of selenoprotein P.  Selenium is transported to the brain mainly by selenoprotein P; defects in the structure and function of this protein result in a sharp decline of selenium levels in the brain and increased urinary selenium excretion.76,131 Selenium deficiency is accompanied by progressive neurological damage, as evidenced by altered spatial memory defects, long-term potentiation deficits in the hippocampus,76 and motor function deficits manifesting as spasticity.130 Selenium deficiency may be fatal if adequate selenium levels are not restored; however, some deficits caused by selenium deficiency may be irreversible, even after aggressive therapy to restore selenium levels.78139

Cognitive performance.  Population studies conducted in Chinese rural communities showed diminished cognitive performance in 2,000 selenium-deficient elderly individuals (= 65 years).140 In addition, alterations in synaptic transmission, short-term plasticity, and hippocampal long-term potentiation (specifically in area CA1) were observed in mice fed a selenium-deficient diet.79 Moreover, under excitatory conditions, an increased number of caspase-3-positive cells (members of the cysteine-aspartic acid protease family141) have been found in selenium-deficient rats.142 In addition, neuronal cell loss in the hippocampus is significantly greater in selenium-deficient rats than in rats fed a selenium-adequate diet.142

Increased oxidative stress.  Selenium is present in certain enzymes that perform antioxidant functions and contribute to the maintenance of redox balance; thus, selenium deficiency may compromise the antioxidant functions of these enzymes. Correlations between low selenium ingestion and diminished antioxidant activity of glutathione peroxidase, as well as its diminished mRNA expression, have been reported.55 Thus, increased cellular susceptibility to damage by oxidative stress, possibly leading to cell death, is an expected consequence of selenium deficiency. Thus far, there is no evidence for deleterious or adverse effects of excess selenium in the CNS or in the limbic system.

CONCLUSION

The essential trace elements iron, zinc, copper, and selenium are cofactors for diverse enzymes involved in structural, metabolic, and antioxidant functions. Furthermore, these elements participate in the synthesis of neurotransmitters, specifically catecholamines. The limbic system, which controls emotions, cognition, and motor functions, has the highest concentrations of trace elements in the brain. Imbalances in the levels of these trace elements are associated with the development of neurodegenerative diseases such as Friedrich's ataxia and Parkinson's, Huntington's, and Alzheimer's diseases, as well as cognitive alterations such as depression, anxiety, and attention and memory deficits.

Acknowledgments

Funding.  This work has been supported by grants from the INSK-2011 (PVR), CONACyT-132621 (PVR), SEP PROMEP/103.5/09/7342 (PVR), and UAEM-1986 (PVR).

Declaration of interest.  The authors have no relevant interests to declare.

REFERENCES

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