Dopaminergic perturbation in the aetiology of neurodevelopmental disorders

Abstract

Brain development may be influenced by both genetic and environmental factors, with potential consequences that may last through the lifespan. Alterations during neurogenesis are linked to neurodevelopmental cognitive disorders. Many neurotransmitters and their systems play a vital role in brain development, as most are present prior to synaptogenesis, and they are involved in the aetiology of many neurodevelopmental disorders. For instance, dopamine (DA) receptor expression begins at the early stages of development and matures at adolescence. The long maturation period suggests how important it for the stabilization and integration of neural circuits. DA and dopaminergic (DAergic) system perturbations has been implicated in the pathogenesis of several neurological and neuropsychiatric disorders. The DAergic system controls key cognitive and behavioural skills including emotional and motivated behavior through DA as a neurotransmitter and through the DA neurons projections to major parts of the brain. In this review, we summarise the current understanding of the DAergic system’s influence on neurodevelopment and its involvement in the aetiology and progression of major disorders of the developing brain including autism, schizophrenia, attention deficit hyperactivity disorder, down syndrome, and fragile X syndrome.

Introduction

Genetic and/or environmental perturbations during neurodevelopment can lead to long lasting neuro-dysfunction which in turn may cause neurological disorders later in life [1]. For instance, alterations during neurogenesis, namely the formation of new neurons during foetal life, may lead to neurodevelopmental cognitive disorders [2]. Several central neurotransmitters including dopamine (DA) play significant roles during brain development and understanding their roles is vital for the understanding the aetiology of neurodevelopmental disorders. Furthermore, considering the role of DA in brain development, it may serve as key target of pharmacological interventions in disorders of the developing brain [3]. DAergic neurons are scattered within the midbrain and their axons project to major parts of the brain, including the cortex and various part of the striatum where they influence key behaviour, including emotional and motivated behaviours [4]. Most neurotransmitters, including dopamine, are synthesized prior to synaptogenesis; hence the potential of altered connectivity by activation of DAergic receptors may occur at early developmental stages [5,6]. Similarly, increased proliferation of DAergic cells during embryonic development can lead to hyperdopaminergia, which results from altered heparan sulphate metabolism [7]. While the expression of DA receptors begins at the early stage of development, their maturity extends to adolescence with a stable pattern at adulthood. Due to this prolong period of expression, disruption at any time during development can lead to several defects or disorders [8]. The delayed maturation of DAergic receptors also suggests its importance in stabilizing and integrating functions on neural circuits [3,9]. DA has roles in various neurological conditions through its modulation of target neuron responses and altered synaptic plasticity. Alteration in basic neuronal processing mechanism and anatomical sites will influence the symptoms and manifestation of the disorder [10,11]. Perturbation of DA signalling has a lasting effect on both behavioural and physiological functions [12]. In this review, we summarise current understanding on the DAergic system, how it influences neurodevelopment and its involvement in the aetiology and progression of neurodevelopmental disorders.

Dopaminergic Neurons and Pathways

Disruption of DAergic circuits can occur through developmental insult or pathological stressor. For instance, post-weaning social isolation in rodents results in neurochemical imbalance with neuroanatomical correlates such as increase in presynaptic DA function at the nucleus accumbens (NAc) and Amygdala [13]. Therefore, understanding DAergic circuit could be vital to therapeutic approaches for disorders arising from the dysregulation of DA patterns [14].

DAergic neurons are localized anatomically at the diencephalon, the midbrain, and the olfactory bulb. The majority of these neurons are at the midbrain region and are the main source of dopamine in the central nervous system [15]. Midbrain DAergic neurons originated from the most ventral midbrain floor plate [16,17] and consist of three major groups of nuclei anatomically, which are already present at gestational day E11-E18 in rodent and week 6–11 in human [18–20].. In rodents, the development of the striatal DAergic innervation occurs at the same time when striatal neurogenesis and cell differentiation commences during embryonic day 14 and by birth, the prefrontal cortex has received high concentration of DAergic innervation with full maturation at early adolescent while the development of human midbrain is believed to follow similar patterns in rodents [19]. The DAergic neurons located at the zona compacta of the substantia nigra (SNpc) A9 area projects to the caudate putamen/dorsal striatum through the nigrostriatal pathway and regulate voluntary movement, goal oriented behaviour and habit learning. Medial to the SNpc is the group that are involved the regulator of memory, reward, motivation, and emotion from the ventral tegmental area (VTA) A10 group. The VTA DA nuclei project to the prefrontal cortex, the ventral/associative striatum, and the limbic system through both the mesocortical and mesolimbic pathways collectively known as the mesocorticolimbic pathway. The third midbrain group of nuclei are in the retrorubral field; A8 group that project from arcuate nucleus and periventricular nucleus of hypothalamus to pituitary gland through the tuberoinfundibular pathway. This pathway controls motivation, emotion, addictive behaviour, stress [21]. Molecularly, there are multiple distinct subtypes of DAergic neurons which all shares same genetic core programming with major function in the production of dopamine neurotransmitter [22–24].

The SNpc and the VTA groups of neurons form two diffuse modulatory systems with broadly scattered connections in the brain and shows difference in firing rate of neurons at different region of their projection [25]. They therefore modulate large number of postsynaptic neurons capable of influencing key behavioural aspects and controls the release of dopamine neurotransmitter [4]. Though it is the proportion of active DA neurons in the VTA that is usually set as the reference tenor of responsivity of the DAergic system [3], the fast synaptic action of DA neurons extends across all the region of the striatum [26]. The striatal DAergic system maturation extends till adolescent though it begins early in development [27]. Dysfunctions in neurons and dopamine release in the SNpc, VTA region, hippocampus, striatum and prefrontal cortex results in the overall dysfunction of the DAergic system [28]. Dysfunction in the mesocorticolimbic circuit and nigrostriatal circuits may lead to social deficits and stereotype behaviour present in autistic and non-autistic subjects [29] though another study suggested that dysfunction in SNpc system alone may result in social deficit and stereotype behaviours [30].

The DAergic system, although structurally distinguishable from other neurotransmitter systems, interacts with the latter systems to control complex behavioural tasks. For instance, neurotransmitter system such as the glutaminergic, GABAergic, cholinergic and other monoaminergic neurons give input to the VTA and SNpc, thereby enriching the pathway with additional neurons other than the DAergic neurons [31–33]. Both human and animal studies has shown that the medial VTA have both DAergic neuron and glutamate neuron, and both plays role in aversion processing [34,35]. Also, the GABAergic neurons present around the dopaminergic DAergic system have different origin from the DAergic neurons itself and the rest of the GABAergic neurons within the brain [36]. Interestingly, the tangential migration of GABAergic neuron precursors within the telencephalon is regulated by activation of dopamine receptors [37] and glutamate serve as a co-neurotransmitter for some population of DA neurons in the SNpc and VTA [38]. The DA neurons has a monosynaptic connection with the cholinergic interneurons [39], which causes the inhibition of cholinergic interneurons to be control by the outburst of the DA neurons thereby making both system to have an interplay in the control of motor and non-motor behaviour within the striatum [40]. Likewise, the DAergic and the serotonergic nuclei shares a proximity in the midbrain, thereby forming a rostral cluster and overlap near the midbrain and hindbrain junction. Thereby, the serotonergic neurons innervate all the brain regions also innervated by the DAergic neurons even though there is cell specificity in their targets [41].

Dopamine Receptors

DAergic receptors are G-coupled protein receptors (GCPRs) widely expressed in the central nervous system, and five major DAergic receptors have been identified; D1, D2, D3, D4 and D5, Each DAergic receptors has their functions and are localized differently. Though the five receptors are present at the striatum and cortex prenatally, D1 and D2 are more abundant than the rest, with D1 being the most abundant during adulthood [42]. The five DAergic receptors are further divided into two subtypes according to their physiological and biochemical attribution; D1 like receptor family; which consist of the D1 and D5, and the D2 like receptor family which consist of D2, D3 and D4 receptors. The D1 like receptors activate adenylyl cyclase, while the D2 like inhibit adenylyl cyclase [43].

D1 and D5 receptors are mostly expressed in the striatum, nucleus accumbens, amygdala, olfactory bulb, frontal cortex, and the substantia nigra while D2, D3 and D4 receptors and are found in the striatum, lateral part of globus pallidus, core of nucleus accumbens, VTA, amydala, hypothalamus, hippocampus, pituitary and the cortical areas [44,45]. Despite the similarity in the expression and membrane structure of D1 and D5 receptors, D5 receptors have higher affinity to DA than D1 receptors [46].

The D1 and D2 receptors are more densely expressed in the striatum than cortex from embryonic development to adulthood [47]. D1 expression decreases steadily within the cortex after four weeks of postnatal life in rodents [48,49], but with higher mRNA expression in the prefrontal cortex than D2 [50]. At early postnatal days during the critical period of plasticity, D3 receptors are highly expressed in the cortex, while, there is drastic drop in the expression of D4 in the cortex after birth, though it is highly expression during embryonic development [51,52].

Despite variations in expression pattern during neurodevelopment, the DAergic receptors have common functions such as of impulse control, attention behaviour and controls level and action of dopamine [53]. D1 receptors exhibit specialized functions during neurodevelopment. They regulate the development of neurons in the presence of dopamine and are essential in regulating memory, attention, learning, motor skills, reward system, and D2 receptors also control motor activities, attention, learning and memory [44,54]. The D1 receptors in the nucleus accumbens control wakefulness, therefore, making the nucleus accumbens a target area for neurological disorders that involves wakefulness such as schizophrenia (SCZ) [55]. The cholinergic interneurons around the ventral striatum are highly sensitive to DA from the VTA projections as they are enriched with D3 receptors [56].

As mentioned above, the DAergic pathway receives inputs from other neurotransmitter system, with their receptors exerts either inhibiting or supressing effect to the function of the system. For instance, muscarinic acetylcholinesterase receptors of the mesolimbic pathway control the release of dopamine, either by inhibiting or activating the release [57]. Previous studies have shown that rats, primates and human midbrain are intermixed with both dopamine and glutamine neurons [35]. High expression of glutamate markers especially VGLUT-2 and VGLUT-3 has been reported in the VTA projection area of rodents except in the NAc [58]. In addition to the glutaminergic neurons, GABA neurons are present in the VTA and SNpc projection, and they express the vesical GABA transporter [59]. Also, the proximity of the serotonergic nuclei to the DAergic nuclei and their projection to the same region of the brain has caused many researchers to study the functional relevance of the two system. Using optogenetic studies, serotonin neurons functions in carrying out reward information though in the presence of co release of glutamate through the glutamatergic cells in the VTA which is controlled but the DAergic reward circuits [60]. Therefore, the multiple functions of midbrain dopamine neurons are likely to be due to many other neuronal networking around this region and elucidating the role of each neuronal population will put shed light to our understanding of disorders associated with the midbrain [35].

Dopamine and Neurodevelopment

DA’s role during neurodevelopment includes regulation of cell proliferation, migration, and differentiation [61]. DA exerts its functions through its receptors (D1 – D5). D1 and D2 receptors control neurogenesis by acting as opposing modulator. Activation of D1 receptors and blockage of D2 receptors leads to increase in the number of neuronal progenitor cells undergoing cell division [62]. In addition, DA function has been reported to promote neuronal proliferation, as early gestational exposure to DA precursor decrease cell proliferation in several brain regions, such as cerebral cortex and caudate putamen [63]. DA plays a vital role in early development of forebrain synaptogenesis and cortical neural circuitry likewise in maturation and attainment of adult level of cognition due to the DAergic neurons projection and the expression of DA receptors to the developing cortex and striatum [64,65]. Zhang et al 2010 reported changes in striatal and cortical circuity following disruption in DAergic signalling [6]. Additionally, DA modulates maturation of neurons into functional excitatory neurons during embryonic development through the D2 receptor [66], therefore showing that DA regulates the differentiation and migration of cortical GABAergic interneurons [67]. During adolescence, the cortical circuits and maturation of excitation-inhibition balance in the frontal cortex is controlled by pruning of D1 receptors [68]. Alterations in the expression of DAergic receptors or pathways as a result of environmental or social insults particularly during development may contribute to cortical and striatal dysfunctions associated with neurological disorders, such as autism spectrum disorders (ASD), attention deficit hyperactivity disorders (ADHD), schizophrenia (SCZ)[8].

Dopamine and Neurobehavioural Dysfunction

The function of DAergic system varies from control of motor initiation to learning, attention and reward [69,70]. One of the functions of DA is in regulating hyperactive behaviours of immature neurons with training of skilful use of forelimb [71,72]. The influence of DA on motor performance can be either a Go or No-go pathway as increase in DA through activation of D1 receptors increases the response to Go while decrease in DA through activation of D2 receptors leads to No-go response. Therefore, blockage of DA may lead to both D2 receptor-dependent and motor performance impairment [73]. Administration of DAergic antagonist has been associated with impaired motor coordination. Whether in injury or normal state, activation of D1 receptors sustains motor coordination and balance, enhanced executive function, cognitive recovery and attentional function, and enhanced speed of cognitive processing [74]. Dysfunction in the DAergic neurons contributes to apathy, loss of motivation and reduced effectiveness of reward mechanism [75].

Dysfunction in DAergic neurons may lead to mood disorders and motivational deficits. Dopamine has been implicated in mood disorders such as depression and bipolar disorder. Research has shown that changes in DAergic function, including alterations in dopamine receptor density and dopamine transporter activity, are associated with mood disorders [76]. For instance, decreased dopamine release in the prefrontal cortex and the nucleus accumbens has been linked to depressive symptoms [77,78]. Moreover, genetic variations in dopaminergic genes have been associated with mood disorders [79,80], providing further evidence for the involvement of DAergic dysfunction in mood regulation. Epigenetic reprogramming of cortical neuron due to DA receptor signalling dysfunction alters DA level leading to psychotic-like behaviour [81,82].

Dopaminergic System and Neurodevelopmental Disorders.

Due to its presence in multiple brain regions, DAergic perturbation has been implicated in neurodevelopmental and neuropsychiatric disorders. Many factors affects the DAergic system that can leads to alteration in most behavior associated with neurodevelopmental disorders. Perinatal exposure to psychostimulant drugs can alter DAergic signalling, thereby leading the cognitive behaviour later in life [83]. Also, stress, infection and lack of vitamins during development can alters DA signalling [84–86]. Below, we discuss the role of DAergic system to major disorders of the developing brain.

Dopaminergic System and ASD

ASD is a neurodevelopmental disorder with behavioural deficits, such as persistent deficits in social interaction, with restricted pattern of behaviour, activities and interests [87]. ASD has received high attention from the public including scientists due its remarkably high prevalence. Its prevalence is 1 in 100 children worldwide and it is likely to rise [88–90]. Due to the comorbidity with other disease, the aetiology has been challenging. It is agreed that genetic and environmental factors are involved in ASD [91]. In addition to the stereotyped behaviour and display of social deficits which are the core traits of ASD, at the cellular level altered striatal circuitry is a major feature of ASD [92]. The neurodevelopmental hypothesis, hypothesise that prenatal and postnatal exposure to environmental insults especially during the critical window of brain development can be the consequence of ASD development and the timing of the insult correlate with synaptic maturation and connectivity [93]. For instance, prenatal exposure to valproate at different time in animal model has shown social behaviour and cognitive deficits including reduction of prefrontal spine density related to ASD like behaviour as reviewed by Tartaglione et al., 2018 [94]. The behavioural effect of prenatal exposure to valproate acts through most of the neurotransmitter system including the DAergic system as antipsychotic medications reverse the behavioural deficit caused by valproate [95,96]. Furthermore, exposure to broad spectrum antibiotics during the last week of pregnancy and first week of postnatal in mouse shows a cognitive deficit in juvenile male more than in female with reduction in many tight-junction protein and oxytocin receptors at the prefrontal cortex [97].

The development of DA and DAergic system begins during the embryonic days, the system and the DAergic pathways continue expanding and matures till adulthood [27]. The plasticity of the DAergic neurons also depends the DAergic signalling [98]. Studies has shown that perturbation in DA signalling during development has a long lasting impact on the cellular, molecular and behavioural functions of the brain. Most behaviour trait observed in ASD are controlled by the mesocorticolimbic circuit and the nigrostriatal circuit of the midbrain DAergic system, these circuits performs cascade of behavioural functions as previously described. This suggests that autistic traits arise from alteration in dopamine signalling around the brain regions where these circuits are formed. Lesion in nigrostriatal circuit and increased in striatal volume has been reported in genetic models of ASD which suggest a determining role for the DAergic dysfunction of the NS pathway in eliciting autistic-like behavior [29]. Study by De Risi et al., 2021 shows that DAergic neurodevelopmental perturbation through increase in proliferation of midbrain DAergic neurons that develops during embryogenesis is associated to ASD like behaviour which was reversed after administration of dopamine like receptor antagonist [7].Evaluation of functions of various neurotransmitters at early stages of brain development has been a focus in studies on neurodevelopmental disorders [99]. A variety of neurotransmitter systems have been implicated in the onset and progression of ASD. There have been somewhat contradictory reports on the contributions of dopamine. Clinical and preclinical studies have reported alterations in DA levels in the ASD-related behavioural deficits [99,100]. On the other hand, Schalbroeck et al., 2021 reported that no significant changes in dopamine synthesis were noted between ASD and a control group within the striatum and its sub region. However, the authors noted that dopamine synthesis is just one aspect of dopamine signalling [101]. Reduced DA content in the prefrontal cortex with reduced neural response in the nucleus accumbens is a common feature of altered DAergic pathways [102]. Increased DA content was reported in newborn mice, exposed as foetuses to DA precursors [63] and DA antagonist ameliorated ASD-like behaviours [99]. De Risi and colleagues also reported that autistic-like behaviour seen in another disease such as mucopolysaccharidosis is due to striatal hyperdopaminergia which implicates striatal dopamine in ASD [7].

Synergistic effects between D1 and D2 in the NAc have are requisite to ensure typical social behaviour [103]. Di Carlo et al. reported that autism-like behaviour is cause due to higher activation ratio of D1/D2 receptors NAc [30] while another study reported increase in D1 receptor at NAc and dorsomedial striatum with no increase in D2 receptors in this brain region in ASD-like behaviour [7]. The latter also reported that pharmacologic inhibition of D1 receptor during development, but not D2, rescues the autistic-like behaviour [7], supported by Lee et al., who showed that excessive D1 receptor in the striatum of ASD and administration of D1 receptor antagonists can restore autism-like behavioural phenotype [104]. Another study reported increase in D2 receptor gene expression in ASD patients [105]. In addition, a recent study reported that ST-713 a novel multiple active compound that has high affinity for histamine and dopamine receptors is beneficial in reversing several ASD-like behavioural symptoms in animal model as it targeted CNS histaminergic and DAergic neurotransmission [106]. Furthermore, though DAergic dysregulation is part of molecular and cellular sign of ASD, there is no common pattern in changes in the number of DA neurons, morphology, excitability, or synthesis and release of DA due to alterations in the DAergic system in ASD – reviewed in [107] (See Fig. 1).

Fig. 1:

A schema of dopaminergic system pathophysiology in neurodevelopmental diseases (ASD, SCZ, ADHD). ASD; Autism spectrum disorder; SCZ: Schizophrenia; ADHD: Attention deficit hyperactive disorder; DA: Dopamine; D1, D2, D3, D4, D5: Dopamine receptor types; NAc: Nucleus accumbens; DM: Dorsomedial; PFC: Prefrontal cortex; BTBR: Autism model; TH: Thyroxine hydroxylase; mRNA: micro-RNA. (Illustration created with Biorender.com)

Chao et al. employed a Black and Tan BRachyury (BTBR) mice model of autism to examine altered dopaminergic pathway in the substantial nigra, ventral tegmental area and the striatal region. They reported that BTBR mice exhibit hypoperfusion of the DAergic system through reduced expression of thyroxine (TH) in both the cell bodies and axon projections of DAergic neurons in most of the nuclei compared with wild type animals, with reduction in the expression of DA transporter (DAT) [92]. This is supported by work of De Risi et al, where an increase in TH+ and NeuN+ cells in early developmental life of mucopolysaccharidosis mice model who display autistic-like behaviour was noted [7]. Other perspectives to DA system dysfunction in ASD mice models are characterized by decreased motivation for social and food rewards in operant conditioning tasks with less social conditioning place preference [92].

Dopaminergic System and Schizophrenia

ASD and SCZ share multiple aetiologies, similar risk factors, same phenotypic features, and co-occur in elevated rate, but they are believed to be two separate disorders – reviewed in [108]. SCZ is a mental heterogenous disorder with characteristics of positive symptoms (hallucination and delusion), negative symptoms (perception, volition and thought disorders) and cognitive symptoms that usually manifest at late adolescent or early childhood [109–111]. It involves almost all brain regions and no single neurotransmitter systems can adequately explain the symptoms displayed in SCZ patients [112]. In SCZ patients, coexisting differences in DA regulation has been reported and the reason for this is unclear. It is believed to arise from deficit in cortical dopamine and excessive subcortical dopamine [113]

Working memory, which is affected in subjects with SCZ, depends on prefrontal dopamine transmission in both in human and in primates [114,115]. Decrease in brain volume which results from increase synaptic pruning has been associated with SCZ [116,117]. The synaptic density is high during brain development and experience marked decrease during adolescent [118]. However, excessive pruning disrupt the excitatory/inhibitory balance and DA imbalance through increased activation of midbrain dopamine neurons [119]. Increased in susceptibility to pruning effect of dopamine is high during early development and one of the ways to lower the susceptibility to pruning action of DA is by lowering the DAergic signalling [120]. In addition, factors that affect the neurogenesis of subventricular zone which usually occurs postnatally can affect synaptic pruning [121]. The failure of prefrontal circuit in SCZ might be due to disruption in the spike timing and synaptic plasticity [122]. In healthy patients and in rodents, D1 receptors are more expressed than D2 receptors [123] but decrease in D1 receptors expression has been noted along the mesocortical projections at the prefrontal cortex of patients with SCZ, likely contributing to impaired working memory [124]. Furthermore, in an in vivo study using monocyte derived neuronal like cell from SCZ patients shows less expression of D1 receptors after exposure to DA [120]. In contrast, another study shows that the expression of D1 receptor at the temporal and parietal cortex of SCZ subjects increases [125]. Vuillermot et al reported increase in the expression of both D1 and D2 receptors at the NAc, but increase in only D1 at the distal striatum [126] and reduction in D2 receptor during adolescent in offspring with maternal induced infection SCZ mice model [127]. D2 knock out mice model has shown increased dendrite density with association to synaptic punning during adolescence which leads to anxiety like behaviour [128]. D3 are densely expressed in the ventral forebrain, while D2 receptors are largely expressed in the striatum with presence of more dopamine transporter around the sensorimotor striatal in SCZ subject [123,129,130].

In an in vivo study, deficit in DA release extended from distal prefrontal regions to extrastriatal regions and the midbrain in SCZ patients [131]. In addition, deficits in frontostriatal thalamic pathway in cognition in SCZ have been reported upon antipsychotic drug treatment, leading to decreased hyperactivity of DAergic neurons along the mesolimbic pathway [132]. Alteration in central aminergic neurotransmitters function along the mesolimbic areas accompanied with neurobehavioural alterations such as those inherent to SCZ have also been reported in post weaning isolated rodent [13]. This implies that social isolation during development of the DA system during childhood may affect the DA circuit thereby leading to neurological disorders in later life. Other environmental factors such as exposure to perinatal maternal stress, neonatal vitamin D deficiency, adverse prenatal nutrition has been reported to be associated with development of SCZ [133,134]. Animals whose mother were exposed to stressor during gestation present a deficit in working memory and reduced N-methyl-D-aspartate (NMDA) receptor expression [135]. Deficiency in vitamin D is related to altered brain volume and maturation of DAergic system [136,137]. Vitamin D receptor are found to be present in substantial nigra and midbrain which are the region that is rich in DA and its receptors [138]. Animal experiment has shown that deficiency in vitamin D leads to psychiatry neurobehavioral deficit later in life [139]. Furthermore, higher risk of up to 44% of developing SCZ has found in neonate with Vitamin C deficiency [140,133]. A recent study has reported increased mRNA levels of D2 receptor gene in neonatal that persist till adulthood in the prefrontal cortex and is associated with cognitive and social impairment in prenatal exposed tetrahydrocannabinol SCZ rat model. This high mRNA level of D2 receptor gene was also present in patients with SCZ [141] (See Fig. 1).

Dopaminergic System and Attention deficit hyperactivity disorder ADHD

ADHD is a highly heritable neurodevelopmental disorder with age-inappropriate persistent symptoms such as inattention, hyperactivity and impulsivity that manifests at childhood and can persist into adulthood in about 35% of patients [142,143]. It is the highest heritable disorders among the psychiatric disorders and it is more common in male than in females, with up to 80% of patients showing comorbid psychiatric disorders and development of secondary problems during adulthood [46]. It is a polygenic disorder with several genes involved in the disorders and it affects the morphology of several brain region including delayed cortical thickening of the prefrontal cortex [144–146]. These changes in ADHD brains lead to developmental impairment [147] which can be due to phasic/tonic imbalance in DAergic system [148]. In a transgenic model of Adgrl3−/− mice; one of the genes implicated in ADHD shows behavioural deficit such as hyperactivity, increased impulsivity among other deficits with highly significant downregulation of soluble family 6, member 3 (Slc6a3) gene encode for DAT in the prefrontal cortex when compared with other brain region [149]. These behavioural patterns has been reported in DAT knock out models [150–152]. Analogous to other developmental disorders previously mentioned, dysregulation of many neurotransmitters including DA system has been implicated in ADHD [153]. Dysregulation of the DA pathways seems to occur during the early stage of brain development [147]. Psychostimulants such as amphetamine, methylphenidate and cocaine are DAT target as DAT blocker or as DA inhibitor uptake within the prefrontal cortex [154]. Administration of single dose of methamphetamine at adulthood after early adolescent co- exposure to amphetamine, methylphenidate and cocaine to hypertensive rat model of ADHD at early adolescent leads to behavioural alteration that persist till adulthood indicating lasting plasticity of DAergic pathways [155]. Amphetamine and methylphenidate are usually prescribed for children with ADHD. Furthermore, Amphetamine induced striatal DA response was shown to have effects on the thickness of frontal cortices [156]. Perinatal exposure to DA precursor _L-DOPA has shown to induce behavioural alteration such as anxiety and depression like behaviour in rat when administered at postnatal day 1–5, which is more significant in female than in male [157]. Another study in ADHD children shows a correlate between cortical thickness of the lateral prefrontal cortex and 10 repeat DAT1 allele [158]. Also, report has shown DA receptors alterations at several brain regions (prefrontal cortex, corpus callosum and caudate) of ADHD patients and genetic models [159,160,152]. Assessing hyperfunctioning of DAergic system early may prevent atrophy of striatum and alterations in neural network in ADHD children [161], as most of the genes associated with ADHD during development plays a vital role in the formation and activity of synapses [147,149]. During development, reduction in DAergic function with variations in the expression of specific genes of DA neurotransmission in nigrostriatal system of ADHD model animals has been reported to be associated with the aetiology of the disorder [162,163]. In addition, a systemic meta-analysis review on the role of dopamine receptor gene in ADHD shows that DA receptor D4 and D5 are the major ones implicated in ADHD [46] (See Fig. 1).

Dopaminergic System and Down Syndrome

Down’s syndrome (DS) is one of the most common neurodevelopmental disorders with approximately 8 million individuals globally been a carrier of extra trisomy 21. It is caused by extra copy of trisomy 21 (T21) and it is the most prevalent genetic condition linked to learning disabilities [164,165]. Delays in development of language and speech as well as problems with spatial and long-term memory are all symptoms of T21 in individuals [166]. Such deficiencies are linked to neuroanatomical problems such as decreased brain weight and size, delayed lamination, and aberrant dendritic and spine formation [167,168]. Further, D1 receptor controls this cognitive behaviour as D1 knock out model has shown to present with spatial learning and spatial working memory deficit [169] and administration or activation of D1 antagonist improves many cognitive deficits [170,171]. Variation in DA levels has been reported in both human and animal models of DS, implicating DAergic dyshomeostasis in DS [172]. Alterations in stems cells destined to develop into DAergic neurons is one of the pathophysiological mechanism of cognitive impairment in DS [173]. Reduction in cortical dopamine level among other neurotransmitters such as serotonin and reduction in D1 receptors complex at the frontal cortex were reported in fetal brain of DS as early as gestational week 20 when compared with control matched brain [174,175]. D1 receptor complex execute major functions of the brain [175]. Upregulation of dopamine transporter 1, with downregulation of vesicular monoamine transporters 2; key regulators of DA homeostasis in dopamine neurons were also reported in DS in a study that employs deciduous teeth derived stem cell. The author also reported reduced number of branches with shorter neurite length in DAergic neurons when compared with the control [176]. The mechanism through which extra T21 present in DS affects the DAergic system and the development of neurite might be by dysregulation of DA transporter by upregulating DAT1 which may then lead to oxidative stress rather than a direct effect on cell survival and differentiation pathway [176]. Also, over-transmission of an allele related to D4 receptor was seen in DS population [177] (See Fig. 2).

Fig. 2:

A schema of dopaminergic system pathophysiology in Down syndrome (DS) and fragile X syndrome (FXS). FMR1−/− : FMRP-deficient mice; DA: Dopamine; D_R: Dopamine receptor; PFC: Prefrontal cortex; cAMP: Cyclic amino monophosphate; AMPH: Amphetamine; WT: Wild-type (control). (Illustration created with Biorender.com)

Dopaminergic System and Fragile X Syndrome

The most prevalent genetic cause of mental disabilities is fragile X syndrome (FXS), which is frequently accompanied with autism and ADHD [178]. It is typically brought on by a deficiency in the fragile x mental retardation protein (FMRP) protein, which is produced by the FMR1 gene on the X chromosome. The majority of research corroborates that FMRP is a selective RNA-binding protein that regulates the translation of its specific messenger RNAs, despite the fact that its mechanism is poorly understood [179]. However, although certain physical and behavioral traits of FXS are suggestive of malfunction in DA-releasing neurons, the neurotransmitter DA is not included in this seemingly straightforward summary of FMRP activity. DA has traditionally been thought of as a crucial modulator of behaviors such as reward-seeking and controlled movement. There is minimal evidence to support a relationship between aberrant dopamine signaling and the pathophysiology or symptoms of FXS since these brain functions are not necessarily compromised in this disorder [179]. Numerous behavioral studies point to DAergic systems’ potential role in FXS. A diagnostic indicator of DA function, spontaneous blink rates, has been shown to be higher in FXS boys than in controls, suggesting that dopamine dysfunction may be implicated in the pathophysiology of FXS, thus warranting further studies [180]. Studies have attempted to clarify how FMRP influences DAergic signaling [181]. By analyzing mice deficient in the Fmr1 gene (Fmr1−/−), a typical experimental model of FXS, these studies investigated the potential link between DA signaling and FMRP activity. They specifically examined the role of the D1 subtype of dopamine receptor within the prefrontal cortex (PFC). Along with modulating glutamate receptor trafficking, the D1 receptor also influences long-term potentiation, a kind of synaptic plasticity believed to be essential for memory formation and retention. Functions commonly regulated by the D1 receptors, such as cellular expression and phosphorylation of the GluR1 glutamate receptors, appeared diminished in the culture-grown PFC neurons of Fmr1^−/− mice. The capacity of a D1-receptor agonist to increase cAMP levels in PFC neurons was diminished in Fmr1−/− mice (Figure 2). When an adenylate cyclase direct activator was administered, these animals failed to exhibit a deficit in cAMP synthesis. Taken together with other findings, these suggest that FMRP is essential for D1 receptor binding to stimulatory Gs proteins. D1 receptors can be phosphorylated at a number of amino acid residues by kinase enzymes called GRKs, this reducing the receptors’ capacity to bind to Gs [181].

When comparing knockout mice to their full genome counterparts, amphetamine (AMPH), a dopamine uptake inhibitor and release stimulator [182] have frequently been utilized to examine behavioral trait differences [183,184]. In order to better understand FXS, Fulks et al. [185] examined the connections between amphetamine-induced behavioural changes and DA release and uptake patterns in Fmr1 knockout (Fmr1 KO) mice. They showed that Fmr1 KO mice displayed less concentrated stereotypy than wild-type (WT) control mice following amphetamine exposure. Furthermore, they reported that DA per pulse and the actual capacity of DA uptake were lower in Fmr1 KO mice than in WT mice at 15 and 20 weeks of age. DA receptors in both genotypes showed identical affinity for amphetamine, according to analyses of dopamine uptake taken at varying concentrations of amphetamine [185]. Overall, their study indicated that impaired dopamine (DA) release and decreased AMPH-induced DA efflux may contribute to resistance in Fmr1 KO mice, and that modulating DA signalling could be a therapeutic approach for FXS (Figure 2). Catechol-o-methyltransferase (COMT); a key enzyme involves in the metabolism of dopamine and other catecholamine have been reported to be associated with many psychiatric disorders and cognitive functions [186–188]. A slower degradation and high dopamine expression in the PFC was noticed due to reduced enzymatic activity of a substitute of COMT [189] and this substitute of COMT has been implicated in many psychiatric disorders including SCZ according to meta-analysis study [190,191]. A recent study uses human pluripotent cell derived from Fmr1 KO and FXS neuron reported that the mechanism through which dopamine signalling is affected in FXS might be through the downregulation of (COMT) due to the loss of FMRP [192]. Likewise, loss of FMRP shifted the trajectory of the cellular properties of spiny projection neuron D1 and D2 at the NAc [193].

Conclusion

Understanding the aetiology of neurodevelopmental disorders and the role imparted by neurotransmitters are promising factors in pharmacological intervention. The development of the DAergic system and the release of DA starts as early as in utero, which makes this system an important player in the pathogenesis of most neurodevelopmental disorders. In addition, the wide network of DA system within the central nervous system reflects its involvement in several behavioural conditions associated with neurodevelopmental disorders. Among all DA receptors, D1 and D2 receptors are the most affected receptors in the control of perturbation that may be associated with DAergic system thereby being the most affected in neurodevelopmental disorders as highlighted in this review.

Data and material availability

Not applicable.