**2. Role of zinc in the brain**

#### **2.1 Role of zinc in neurogenesis and synaptic transmission**

Zinc has a variety of crucial roles in neurogenesis [4]. Zinc deficiency decreases the neurogenesis process and impairs the expression of genes involved in hippocampus proliferation and neuronal development in the postnatal rat cerebellum [20]. Further, zinc deficiency reduces the proliferation of the human neuroblastoma cell line, promotes apoptosis, and inhibits retinoic-acid-induced neuronal development in cultured cells [1, 21].

Of note, zinc is found in the presynaptic glutamatergic vesicles across the brain, including the cerebral cortex, limbic system, hippocampus, and olfactory bulb [22].

It acts as a neuromodulator on a wide range of membrane receptors, ion channels, and transporters [23]. Synaptic zinc, in particular, is enhanced via a specialized zinc transporter, ZnT3, and is coreleased with glutamate during action potential-induced exocytosis [24]. These also have an impact on synaptic transmission, which interacts with receptors and channels that regulate auditory processing [25, 26]. Synaptic zinc has been discovered to inhibit NMDA receptors, GABA-A receptors, and calcium channels while activating AMPA and glycine receptors [27–30]. Zinc also has vital effects on other kinds of receptors, including serotonin, dopamine, and acetylcholine receptors, as well as voltage-gated ion channels for sodium, potassium, calcium, and chlorine [29, 31].

Synaptic zinc regulates sensory processing and improves acuity in the discrimination of different sensory stimuli. Synaptic zinc plasticity leads to prolonged adaptations and sense memories. Recently, the mechanism of this long-term synaptic

zinc plasticity has been described as being due to group 1 metabotropic glutamate receptors (G1 mGluRs)-dependent mechanism that triggers a bidirectional long-term change in synaptic zinc signaling [32].

#### **2.2 Role of zinc at depression**

No one denies that depression treatment is a gateway to overcoming many social and psychological problems that affect millions of people all over the world. Many factors play a role in depressive-like behaviors, such as impairment of functions of the hippocampus and the prefrontal cortex. These brain parts play an important role in decision-making processes, so any dysfunction at this area can induce a predisposition to negative feelings, and many glucocorticoid receptors are involved in these areas [33].

In terms of both pharmacological and clinical/epidemiological data, recent years have provided additional evidence confirming the role of zinc in depression. Zinc demonstrated antidepressant-like efficacy in preclinical studies and depressive models. Clinical evidence suggested that zinc supplementation might be beneficial in people suffering from depression. Zinc supplementation has been demonstrated to be beneficial as adjuvant therapy or as a stand-alone intervention for depression. Furthermore, zinc consumption has been linked to an increased risk of depression. Dietary zinc restriction was found to be a causal factor in the development of depressive-like symptoms or anhedonia in mouse studies [34]. Some epidemiological studies have reported that reduced nutritional zinc consumption is related to depression in females but not in males [35]. Even though the first prospective study examining the relationship between zinc intake and depression risk found a small but significant inverse correlation between them, a 20-year follow-up study found that a reduced dietary zinc intake protects from depression in men who were not previously depressed. However, because the research participants were all men with a hospital discharge diagnosis of unipolar depression, the findings cannot be applied to women or patients who did not require hospitalization. On the contrary, a reduced nutritional zinc intake was found to be a risk factor for depression in a prospective analysis of both men and women [36]. Mice missing the G-protein-coupled receptor 39 (GPR39), a zinc-activated receptor, show depressive-like behavior [37]. TC-G-1008, a GPR39 agonist, was recently discovered to have antidepressant-like effects [38]. These findings add to the growing body of evidence that zinc is useful in the treatment of depression.

Meta-analyses support the use of zinc as a supplement in the treatment of severe depression, and single research currently supports the use of zinc for psychotic symptoms [39]. Zinc deficiency has also been linked to neuropsychiatric symptoms such as altered behavior and cognition, learning difficulties, and depression [40–42].

The link between zinc dysregulation and psychiatric disorder was that zinc acts as an inhibitory modulator at the NMDA glutamate receptor [43–45]. In addition, the inhibitory effects on the nicotinic acetylcholine receptor (nAChR), GSK3 (glycogen synthase kinase 3beta), and NOS (nitric oxide synthase) are also relevant to depressive processes [46, 47].

Numerous studies show lower zinc blood levels in depressed people compared with healthy people, with a meta-analysis showing depressive symptomatology at zinc serum levels of 1.8 M or below [48]. In several investigations, zinc supplementation enhanced mood in those who were suffering from treatment-resistant depression [41, 49].

Zinc's effect on the brain-derived neurotrophic factor (BDNF), a growth factor that promotes neurogenesis and differentiation, may be connected to depression. The hippocampus is a center of lifelong neurogenesis, and periods of significant

depression are associated with reduced BDNF expression and neuro/synaptogenesis. Rodents on a zinc-deficient diet had lower zinc levels in the hippocampus vesicles, a part of the brain where zinc levels are generally greater, as well as lower amounts of progenitor cells and immature neurons. Zinc-rich diets, on the other hand, increased amounts of progenitor cells [3, 41]. The GPR39 receptor is most likely a critical connection in the interaction between zinc and the serotonergic system, which is required for antidepressants that affect the serotonin pathway to work [34].

#### **2.3 Zinc and neuroimmunity**

Of note, laboratory animal models showed that zinc insufficiency induces thymus and lymphoid tissue atrophy. It lowers the number of spleen cells and the sensitivity to antigens that are both T-cell-dependent and -independent [50]. Microglia is a kind of immune cell found in the central nervous system (CNS) [51]. The link between zinc and microglial activation reflects an undiscovered process that may play a role in neuropathy. However, zinc is produced by neurons under several conditions to activate microglial [52].
