Influence of Serotonin on the Development and Migration of Gonadotropin‐Releasing Hormone Neurones in Rat Foetuses

Abstract

This study used a pharmacological approach to evaluate the consequences of the metabolic perturbations of neurotransmitters on brain development. Pregnant rats received p‐chlorophenylalanine (pCPA), an inhibitor of serotonin (5‐hydroxytryptamine, 5‐HT) synthesis, or saline (control) from the 11th day of gestation once or daily up to the 15th, 17th and 20th day, followed by processing of the forebrain and/or nasal cranium of foetal males and females for high‐performance liquid chromatography of monoamines, radioimmunoassay of gonadotropin‐releasing hormone (GnRH) and quantitative and semiquantitative immunocytochemistry for GnRH. The pCPA treatment resulted in a 50–70% depletion of 5‐HT in the nasal crania and forebrains at any studied age. Radioimmunoassay showed no change in GnRH content in 5‐HT deficient foetuses at E16 compared to controls, being higher in both cases in the rostral forebrain than in the hypothalamus. In controls at E21, the GnRH content in the hypothalamus exceeded that in the rostral forebrain, whereas in the 5‐HT deficient group the opposite was found. These data suggest that 5‐HT provided a stimulating effect on GnRH neurone migration, and this was confirmed by quantification of GnRH‐immunoreactive neurones in the forebrain along the trajectory of their migration. At E18 and E21, the fractions of GnRH neurones in the rostral part of the trajectory in pCPA‐treated foetuses were greater than those in control foetuses but the opposite was true for the caudal part of the trajectory. Moreover, 5‐HT appeared to control the proliferation of the precursor cells of GnRH neurones and their differentiation, as derived from the observations of the increased number of GnRH neurones in the forebrain of foetuses of both sexes, as well as the region‐specific decreased neuronal size and content of GnRH in 5‐HT‐deficient females. Thus, 5‐HT appears to contribute to the regulation of the origin, differentiation and migration of GnRH neurones.

Cholecystokinin Modulates Migration of Gonadotropin-Releasing Hormone-1 Neurons

“…The crossover from nasal region to CNS is a dramatic change in environment, and it has been suggested that such a pause may ensure appropriate maturation of GnRH-1 neurons, allowing them to respond to new molecular cues (for review, see Wray, 2002). To date, several molecules have been shown to alter the GnRH-1 migratory process, including GABAergic, serotoninergic, and glutamatergic signals (Fueshko et al, 1998;Bless et al, 2000;Simonian and Herbison, 2001;Heger et al, 2003;Pronina et al, 2003a).…”

CXCR4/SDF‐1 system modulates development of GnRH‐1 neurons and the olfactory system

“…For example, within the nasal region, neural cell adhesion molecules (NCAM; Gong and Shipley, 1996), netrins (Shu et al, 2000), semaphorins (Gavazzi, 2001), EphB2 (St. John and Key, 2001), NELF (Kramer and Wray, 2000a), and CCK (Giacobini et al, 2004) have been identified to influence, either directly or indirectly, olfactoryvomeronasal axon outgrowth and GnRH-1 neuronal migration. At the nasal forebrain junction/cribriform plate, new molecular players appear, i.e., GABA (Fueshko et al, 1998;Bless et al, 2000), glutamate (Simonian and Herbison, 2001), and serotonin (Pronina et al, 2003); while others disappear, i.e., NELF (Kramer and Wray, 2000a). Several of these molecules have been proposed to regulate entrance of the GnRH-1 neurons into the developing forebrain (Wray, 2002).…”

Serotonin stimulates GnRH secretion through the c-Src-PLC γ1 pathway in GT1–7 hypothalamic cells

“…Following earlier reports that implicated serotonin in the development and migration of GnRH neurons (Pronina et al 2003), a great deal of attention has become focused on the role of serotonin in GnRH release (Moguilevsky & Wuttke 2001, Wada et al 2006. The demonstration of synaptic contacts between the serotoninergic system and the GnRH neurons suggested that serotonin could act directly on GnRH release.…”