The Central Noradrenergic System in Neurodevelopmental Disorders: Merging Experimental and Clinical Evidence

Abstract

The aim of this article is to highlight the potential role of the locus-coeruleus-noradrenergic (LC-NA) system in neurodevelopmental disorders (NdDs). The LC is the main brain noradrenergic nucleus, key in the regulation of arousal, attention, and stress response, and its early maturation and sensitivity to perinatal damage make it an interesting target for translational research. Clinical data shows the involvement of the LC-NA system in several NdDs, suggesting a pathogenetic role in the development of such disorders. In this context, a new neuroimaging tool, LC Magnetic Resonance Imaging (MRI), has been developed to visualize the LC in vivo and assess its integrity, which could be a valuable tool for exploring morphological alterations in NdD in vivo in humans. New animal models may be used to test the contribution of the LC-NA system to the pathogenic pathways of NdD and to evaluate the efficacy of NA-targeting drugs. In this narrative review, we provide an overview of how the LC-NA system may represent a common pathophysiological and pathogenic mechanism in NdD and a reliable target for symptomatic and disease-modifying drugs. Further research is needed to fully understand the interplay between the LC-NA system and NdD.

Keywords: ADHD; autism; childhood epilepsy; developmental disorders; locus coeruleus; neurodevelopment; neurogenesis; neuropediatric; noradrenaline.

Figure 1

The workflow of the literature search is reported in the flowchart. The search was performed on pubmed.ncbi.nlm.nih.gov using the key words reported in the paragraph “Methods”. A final set of 68 papers were used to write the systematic part of the review. * Articles cited as [3,4,5,6,7,8,9,10] are review papers used to provide a clinical and pharmacological background and are thus not included in the final count.

Figure 2

The LC provides a dense and widespread system of projections that virtually reaches the whole CNS. From the anatomical nucleus, NA fibers travels segmented into three pathways: an ascending pathway (ANP) through which the LC reaches the midbrain and the forebrain, a cerebellar pathway (CNP), and a descending pathway (DNP), which carries the NA fibers for the lower pons, the medulla, and the spinal cord. Through such anatomical connections, the LC enters the circuitries of the sleep/wake cycle and circadian rhythms regulatory nuclei and of autonomic system modulatory nuclei. Rostrally, the LC reaches the limbic system and the neocortex, taking part in the complex orchestration of cognitive and behavioral functions, such as attention and memory. (Created with Biorender.com, accessed on 15 March 2023). Abbreviations: ANP: Ascending Noradrenergic Pathway; CNP: cerebellar noradrenergic pathway; CNS: central nervous system; CRN: caudal raphe nuclei; DNP: descendent noradrenergic pathway; DRN: dorsal raphe nucleus; LC: locus coeruleus; LDT: lateral dorsal tegmental nucleus; LHA: lateral hypothalamic area; NA: noradrenaline; PPT: pedunculo-pontine tegmental nucleus; PVN: paraventricular nucleus; RVLM: rostral ventro-lateral medulla; SCN: suprachiasmatic nucleus; VLPO: ventro-lateral preoptic area; W/S: wake and sleep cycle.

Figure 3

The LC-NA system modulates many neural networks (macroscale level) and regulates several homeostatic mechanisms (microscale level) of the central nervous system, many of which are involved in neurodevelopmental disorders. At the microscale level, LC-NA participates in synaptogenesis and synaptic plasticity, both as a neurotransmitter and through modulation of microglia and the promotion of blood–brain barrier integrity. At the same time, NA functions as a regulator of neurogenesis, a role that this system maintains during both pre-natal and post-natal life, up to adulthood. At the macroscale level, the LC-NA system regulates the activity of many neural networks, participating in the sleep/wake cycle and stress response. Moreover, it modulates cognitive functions such as attention and memory. Altered synaptogenesis and abnormal neurogenesis are suggested as possible pathogenetic mechanisms of neurodevelopmental disorders; in parallel, cognitive and behavioral alterations and mood and sleep disorders are common clinical features in these patients. Accordingly, a causal role of LC alteration during ontogeny and postnatal development has been hypothesized. (Created with Biorender.com, accessed on 15 March 2023). Abbreviations: LC: locus coeruleus; LC-NA: locus-coeruleus–noradrenergic System.