Noradrenergic receptor activation alters the migration and distribution of interneurons in the developing neocortex (Commentary on Riccio et al.)


Monoamine (noradrenaline, dopamine or serotonin)-containing fibres form some of the earliest inputs to the developing brain, including the cerebral cortex (Parnavelas et al., 1988). Noradrenaline-containing (noradrenergic) axons arise exclusively from neurons in the locus coeruleus in the brainstem and are distributed widely throughout the cerebral cortex. These axons first enter the cortex at the early stages of corticogenesis as two distinct bundles located in the marginal and intermediate zones, and running tangential to the pial surface (Levitt & Moore, 1979). Fibres arising from the superficial and deep bundles gradually invade the developing cortical plate, with the mature pattern of innervation attained in early postnatal life in rodents (Lidov et al., 1978; Levitt & Moore, 1979). The physiological and biochemical effects of noradrenaline are mediated by two classes of receptors originally designated as a- and b-adrenergic receptors (adra and adrb) and subsequently subdivided into different subtypes. All subtypes of adrenergic receptors have been described in the cortex, and their ontogeny has been documented (Wang & Lidow, 1997).

The early ontogeny of the noradrenergic system has led to speculation that it exerts regulatory functions in the developing cortex, and numerous studies have documented its role in developmental processes and in the maintenance of cortical plasticity (Blue & Parnavelas, 1982; Bear & Singer, 1986; Lidow & Rakic, 1994; Osterheld-Haas et al., 1994). The strong expression of adrenergic receptors during corticogenesis has also led to the hypothesis that these receptors are involved in different developmental process including neuronal migration (Wang & Lidow, 1997). However, concrete evidence that supports a role in cortical neuron migration is lacking.

In this issue of EJN, Riccio et al. describe a novel function for adrenergic receptors in interneuron migration. Using GAD65-GFP transgenic mice and in-utero electroporation, they demonstrate the expression of adra and adrb in cortical interneurons derived from the caudal, but not medial, ganglionic eminence. To study the effects of adrenergic receptor activation on interneuron migration, they used time-lapse imaging in brain slices. They found that activation of adrb receptors with isoproterenol did not alter the speed of migration of labelled interneurons, but activation of adra1 and adra2 receptors with cirazoline and medetomidine, respectively did lead to a reduction in migratory speed. Using more specific adra agonist stimulation [adra2a-guanfacine; adra2c -(+)-m-nitrobiphenyline oxalate], the authors observed a similar reduction in interneuron migratory speed as well as a significant change in the direction of migration. They further confirmed these findings by utilizing adra2a/c knockout lines. Quantification of the distribution of GAD65-GFP cells in these double knockout mice showed significantly altered distribution in the somatosensory cortex at postnatal day 21 compared with control mice, with a pronounced increase of labelled cells in the supragranular layers, suggesting that these adrenergic receptors are essential for the proper positioning of interneurons in the cortex. However, analysis of single (adra2a or adra2c) knockout animals revealed no alterations in interneuron distribution at the same age, suggesting the presence of compensatory regulatory mechanisms. Thus, for the first time, a specific role for adrenergic receptor activation has been postulated in interneuron migration and disposition. However, the intracellular mechanisms that mediate this function remain to be elucidated. The study of Riccio and colleagues represents the first step in the effort to elucidate the role(s) of adrenergic receptors in cortical neuron migration. Pyramidal neurons also express these receptors (Wang & Lidow, 1997), and it will be of interest to assess their role in the radial migration of this larger population of cortical cells. The results so far point to the notion that overstimulation of adrenergic receptors in the cortex by excessive levels of noradrenaline or by drugs may lead to alterations in the formation of neuronal circuits and, consequently, of cortical function.