**9. ACE2 and neurotransmitters involved in adult neurogenesis**

Neurotransmitter signalling is found to play a major role in the formation of new neurons in addition to its clear and indisputable role in communication between neurons. Starting from embryogenesis, neurotransmitters are involved in neuronal proliferation. In adult neurogenesis, they influence various steps including proliferation, differentiation, and migration. In addition to the direct action of neurotransmitters on adult neurogenesis, they also influence other factors that regulate neurogenesis like neurotrophic factors and growth factors [107].

#### **9.1 ACE2 and serotonin**

Serotonin is a crucial monoaminergic neurotransmitter that acts as a mood stabiliser and is associated with feelings of happiness, well-being, and contentedness. In the brain, it is synthesised by the Raphe nuclei neurons in the brain stem from tryptophan using neuron-specific tryptophan hydroxylase 2 enzymes. Vesicular monoamine transporter 2 [VMAT] packs the synthesised serotonin into vesicles. Serotonin transporters [SERT] re-uptake serotonin back to presynaptic neurons after its release, thereby regulating its extracellular levels [108]. The serotonergic fibres from raphe nuclei have projections throughout the brain and especially to the granule cells and interneurons of the dentate gyrus of the hippocampus. Serotonin is known to play a major regulatory role in adult hippocampal neurogenesis. Selective serotonin reuptake inhibitors [SRRI] are commonly used antidepressants that act by increasing serotonin levels in the brain causes clinical improvement associated with an increase in adult hippocampal neurogenesis characterised by increased neuronal proliferation and number of newborn neurons [109]. Malberg et al. in 2000 were the first to show that chronic treatment with fluoxetine improved adult hippocampal neurogenesis [109]. In the dentate gyrus, serotonin is known to promote neuronal development and its depletion was found to cause reduced dendritic spine density of granule cells [110–113]. Chronic treatment with SSRI, fluoxetine was found to increase the survival of newborn neurons in the dentate gyrus [109, 114]. In stress models like inescapable stress, cold restraint stress in the animal model, fluoxetine administration was found to exhibit neurogenic and neuroprotective roles in the hippocampus [114, 115]. Accelerated synaptogenesis and increased long-term potentiation [LTP] in the hippocampus were also observed by long-term treatment by fluoxetine [116].

Recent studies have found that ACE2 plays a major role in the biosynthesis of serotonin [5HT]. The precursor for 5HT is an essential amino acid, tryptophan which can cross the blood–brain barrier and whose intestinal absorption was found to be reduced by 70% in case of ACE2 deficiency. Thus, ACE2 has an indirect modulatory role in 5HT synthesis in the brain [117]. There are recent studies that show that 5HT synthesis in the brain is dependent on ACE2, which acts by modulating 5HT metabolism and ACE2 deficiency leads to decreased serum tryptophan levels and decreased serotonin levels in the brain [94].

#### **9.2 ACE2 and dopamine**

Dopamine is involved in executive functions, volition, motor control, motivation, pleasure/reward, and attention/concentration [118]. The role and mechanism

#### *Does COVID-19 Affect Adult Neurogenesis? A Neurochemical Perspective DOI: http://dx.doi.org/10.5772/intechopen.101179*

of action of dopamine in adult neurogenesis are not elucidated fully. Dopamine was found to modulate cell proliferation in the embryonic brain [119]. Hippocampus and sub-ventricular zone [SVZ] which are the neurogenic niche containing neural stem cells receive dopaminergic projections from the substantia nigra and ventral tegmental area. Dopamine receptors are also widely expressed in these two areas and play a regulatory role in adult neurogenesis and neural plasticity [120, 121]. Earlier studies show that depletion of dopamine in the rat model reduces both proliferation and survival of neural precursor cells in the sub-granular zone [SGZ] of the dentate gyrus [122, 123]. Dopaminergic denervation in substantia nigra caused a significant reduction in the proliferation of neural stem cells in SGZ and SVZ which was reversed by D2 receptor stimulation in rodents [123]. In humans, post-mortem studies have revealed that the number of neural precursor cells in SGZ and SVZ was reduced in patients with Parkinson's disease [124]. Dopamine was also found to increase the type 2A early progenitor cell in the hippocampus of rodents via D1 like receptors [118]. Dopamine receptor agonist pramipexole increases the proliferation and survival of newborn neurons in SVZ, olfactory bulb [119].

RAS plays a major role in dopaminergic vulnerability through AT1 receptors. Dysregulation of RAS due to the downregulation of ACE2 induced by SARS-CoV-2 may increase the vulnerability of dopaminergic neurons and subsequently dopamine levels [125]. Interactions between dopamine and angiotensin receptors that are counterregulatory in nature are observed in substantia nigra and striatum [125]. The gene for ACE2 was found to coexpress and coregulate with that of dopa decarboxylase [DDC] in non-neuronal cells, which is a major enzyme of dopamine, serotonin, and histamine biosynthesis. DDC converts L-3,4-dihydroxyphenylalanine [L-DOPA] into dopamine which subsequently forms norepinephrine and epinephrine and L-5-hydroxytryptophan into serotonin. This coexpression and coregulation link between the genes for ACE2 and DDC gives rise to the possibility of a functional link between the actions of ACE2 and DDC [i.e.,] in the synthesis of Ang [1-7] and dopamine and serotonin mediated by ACE2 and DDC, respectively [126]. Following the infusion of Ang [1-7] in the hypothalamus of rats, brain dopamine levels increased which emphasises the link between ACE2 and DDC. SARS-CoV-2 induced downregulation of ACE2 could cause the decreased synthesis of serotonin and dopamine [94, 127].

The SARS-CoV-2 infection has been found to cause loss of dopaminergic neurons and deficits in the dopamine system [86, 128]. ACE2 expression is high in dopaminergic neurons and the downregulation of ACE2 by SARS-CoV-2 may cause depletion of dopaminergic neurons and dopamine levels. This is evident from the worsening of symptoms observed in COVID-19 patients with Parkinson's disease [PD], requiring increased dopamine replacement therapy [129]. ACE2 deletion in the knockout mouse model caused a significant reduction in dopamine D1 mRNA expression in substantia nigra [130].
