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Zinc deficiency and psychiatric disorders is a novel field of research. Zinc is an essential mineral that may be lacking in processed or vegetarian diets.[1] Biosystems have no special zinc storage capability, so zinc must be ingested regularly.[1][2] Zinc is involved in the brain and body’s response to stress.[1] 300 or more metalloenzymes in the human body utilize zinc, in processes like DNA synthesis, protein synthesis and cell division.[1][3] Zinc ions are an integral component of DNA and RNA polymerase[4] and Zinc finger receptor motifs are vital in cell signaling. Zinc concentrations in the mammalian central nervous system accumulate mostly in the hippocampus and cortical gray matter of the brain.[5][6] Zinc-containing neurons accumulate at the presynaptic vesicles and then release the ions. All zinc-containing neurons are glutamatergic, but not all neurons contain the metal.[7] Zinc transporter 1 (ZnT-1) pumps zinc out of the post-synaptic vesicles while zinc transporter 3 (ZnT-3) serves to pump the zinc in the synaptic vesicles.[8][9] Zinc has anti-inflammatory and anti-depressant activity.[10]

Major Depressive Disorder

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Main article: Major depressive disorder

Zinc is low in serum of those suffering with depression; the more depressed the person, the lower the zinc level.[11] Zinc supplementation has been shown to have anti-depressant effects in humans; successful treatment increases serum zinc levels.[12] Combination of zinc plus modern anti-depressant medication has been shown to be effective.[13] Low Zn2+ levels has been shown to correlate with lowered brain-derived neurotrophic factor (BDNF) protein level, which aids in neuroplasticity and recovery, found in the pathology of depressed patients.[14]

GPR39

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Zinc has been shown to activate neural transmissions via the GPR39 Zn2+-sensing receptor, which may be involved in the regulation of neuroplasticity.[14] The GPR39 protein is expressed in the CA3 region of mammalian hippocampus. Its receptor responds physiologically to concentrations of zinc, initiating metabotrophic signaling following synaptic zinc release, stimulating expression through the Gαs pathway.[15][16] Stimulation of GPR39 upregulates the anti-apoptotic protein clusterin, important due to its expression in the brain in astrocytes and neurons of the hippocampus.[17] GPR39 may play a role in initiating clusterin release that maintains functional frontal-subcortical connectivity, this being often impaired in mood disorders.

Ionotropic NMDA receptors

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NMDA Lewis Structure.
NMDA.
Glutamic Acid Lewis Structure.
Glutamate.

In the synaptic cleft, zinc acts as a modulator of glutamate ionotropic NMDA and attenuates the activation of the NMDA receptors at concentrations in the range 10-100 uM.[18] After release into synaptic cleft, zinc may diffuse into the postsynaptic neuron during excitotoxic brain injury and exhibits both neurotoxic and neuroprotective effects.[19] NMDA receptor complex responds to glutamate by increasing its permeability to calcium. They are heterotetrameric complexes comprised of NR1 and NR2 subunits, whereby each subunit contains an extracellular N-terminal domain containing sites for extracellular molecules modulating the gating of the channels. Zinc inhibits ion channels conductance by binding the allosteric sites of the two common expressed NR2 NMDA receptor subunits (NR2A and NR2B), NR2A having a relatively high affinity than NR2B to zinc.[20] Proliferation of hippocampal neural progenitor cells in the dentate gyrus can be stimulated by NMDA receptor activation. Zinc deficiency impairs NMDA receptor evoked Ca2+ currents by decreasing the number of NMDA receptors.[21]

Zinc binds to NR2B subunits, which are most plentiful in the extrasynaptic NMDA receptors, where a contribution to the influx of Ca2+ is made in the absence of an action potnetial, predisposing cells to excitotoxicity in response to normal stimulus-dependent synaptic glutamate release. Glutamate receptors on astrocytes modulate the expression of glutamate-receptors by controlling the re-uptake of glutamate, regulating extracellular glutamate concentrations.[22] At the postsynaptic neuron, activation of glutamate-receptors results in an increase in Ca2+ levels. Ca2+ binds to Calcium-Calmodulin complex, stimulating the synthesis of nitric oxide (NO).[23] Nitric oxide may be able to stimulate the release of dopamine and norepinephrine.[24] As a result, NO plays a role in the inhibition of endogenous substance in discriminative effects of psychostimulants.[25]

Dementia

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Main article: Dementia
Cartoon representation of the molecular structure of protein registered with 1n5g code, zinc domain of DNA polymerase.
A 3D representation of the Zinc domain of DNA Polymerase[26].

Traditionally, the onset of dementia has been attributed solely to a combination of genetic factors.[3] The treatment of this disease has been focused on voiding or modifying the effect of the contributing gene via inducing change in anatomical structures or biochemical conditions of the body.[3] However, it was argued that in order to truly eradicate dementia one must find a chemical basis which may be modified or blocked with appropriate reagents.[3]

Indirect and direct evidence for the presence of zinc ions in DNA and RNA polymerase has been found for a variety of organisms including rat,[27] rabbit,[28] human,[29] Escherichia coli.,[30][31] and sea-urchins.[29][32] Studies of E. coli DNA polymerase I and AMV DNA polymerase with the chelating agent, O-phenanthroline and its non-chelating analog m-phenanthroline indicate possible catalytic roles of Zn2+ [4]. In particular, it is suggested that Zn2+ aids the action of DNA polymerase by coordinating to the hydroxyl group (-OH) of the 3’ end, facilitating deprotonation and increasing nucleophilcity of the group allowing for an attack on the alpha-phosphorus atom of the incoming nucleotide triphosphate [4]. Based on this information, Burnet hypothesized that occurrence of dementia may be due to decreased fidelity in neuron-based DNA enzymes which have an age-linked loss of ability to make zinc available.[3] This hypothesis was based on indirect evidence but not refuted by related clinical findings,[3] rather it is has been supported by numerous clinical studies.[33][34] The hypothesis suggests that administration of zinc could be used to prevent/delay the occurrence of dementia in individuals. This proposal has lead to a flood of reports concerning the role of zinc in Alzheimer’s disease, the most prevalent form of dementia in modern society.[35]

Alzheimer's disease

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Main article: Alzheimer’s

Currently the possible causes for Alzheimer’s Disease (AD) are thought to involve the formation of plaques and neurofibrillary tangles in the brain. Plaques characteristics of Alzheimer’s are mainly formed from the depositions of amyloid beta (Aβ) peptides (38-42 amino acid residues long). Aβ peptides are formed via a two-step cleavage of amyloid precursor protein (APP) where β secretase cleaves a soluble fragment of APP and γ secretase cleaves a portion of the remaining membrane bound APP yielding the Aβ peptide (see amyloid cascade hypothesis).[36] Aβ proteins are found to bind high concentrations of Zn2+, Cu2+, and Fe3+. They are thought to function like metalloenzymes in the catalysis of reactive oxygen species (ROS) leading to the production of hydrogen peroxide. As a result Aβ peptides have been targeted via chelation therapy where liberation of metal ions from the metal rich plaques are thought to reduce progression of Alzheimer's.[37]

Patients with AD have been found to have deficient serum zinc levels.[38][39] It is thought that Aβ plaques reduce the amount of zinc available in the blood affecting homeostatic regulation of the metal. Therefore studies on zinc homeostasis have been undertaken although further research is needed on the effect of intracellular control via zinc importers (Zip), zinc transporters (ZnT) and thioneins. Metallothioneins are a group of small (62-68 amino acids) cysteine-rich proteins. They bind to Zn2+ and Cu2+ ions playing a role in regulation although their link to neurodegenerative diseases is yet unclear.[40]

Down syndrome

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Main article: Down syndrome

Root cause of Down syndrome is attributed to the presence of an extra Chromosome 21. Patients of Down syndrome have an abnormally low zinc status in body. Impairment of thyroid function, immune dysfunction, and rapid aging are also associated with the syndrome. In the thyroid gland, the main pattern that has been observed in Down syndrome patients is an excess of Thyrotropin, normal levels of Triiodothyronine and Thyroxine, and decreased RT3 levels.[41] Symptoms associated with thyroid dysfunction are closely related to symptoms of Down syndrome. Low RT3 levels due to thyroid dysfunction impairs growth hormone stimulation. Similarly, Down syndrome patients have an elevated TSH which forces severe growth delay.[41] Zinc deficiency in Down syndrome is speculated to be related to thyroid dysfunction; however the specific mechanism is unknown. Although, zinc supplementation has shown to bring Thyrotropin levels to a normal, therefore it is certain that zinc is involved in the thyroid pathways. One explanation is that thyroid hormone receptors need Zn2+ to facilitate folding into their active shape.[42] Zinc is also used for binding thyroid hormone receptors to their thyroid response elements.[42]

Thymulin.
Thymulin Hormone secreated by the Thymus Gland

Defective immune system of DS subjects can be monitored by thymic function.[43] A reduction in T Lymphocytes, B-lymphocytes, and diminished hypersensitivity is due to low levels of zinc causing atrophy of the thymus. This occurs because zinc is required for Vitamin A transport from liver; Vitamin A is a requirement for growth hormones which maintain thymus activity. Thymulin activity provides an accurate measure of thymic gland function, and studies on thymulin activity in DS reveal inhibition by biologically inactive thymulin via binding to thymulin receptor sites. Zinc is an activating agent for thymulin and zinc supplementation is known to decrease thymulin inhibition while at the same time increasing active thymulin in DS subjects.[44]

Down syndrome subjects experience premature aging suggestive of a faulty DNA repair system. After DNA damage, persistent oxidative stress results in a greater rate of activation of DNA repair enzymes in DS subjects.[45] Oxidative stress is due partially to zinc deficiency and correction via zinc supplementation results in a significantly reduced frequency of DNA repair to a healthy rate.[45]

References

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Category:Zinc Category:Mineral deficiencies Category:Mental disorders

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