Disruption of the serotonergic system after neonatal hypoxia-ischemia in a rodent model

Abstract

Identifying which specific neuronal phenotypes are vulnerable to neonatal hypoxia-ischemia, where in the brain they are damaged, and the mechanisms that produce neuronal losses are critical to determine the anatomical substrates responsible for neurological impairments in hypoxic-ischemic brain-injured neonates. Here we describe our current work investigating how the serotonergic network in the brain is disrupted in a rodent model of preterm hypoxia-ischemia. One week after postnatal day 3 hypoxia-ischemia, losses of serotonergic raphé neurons, reductions in serotonin levels in the brain, and reduced serotonin transporter expression are evident. These changes can be prevented using two anti-inflammatory interventions; the postinsult administration of minocycline or ibuprofen. However, each drug has its own limitations and benefits for use in neonates to stem damage to the serotonergic network after hypoxia-ischemia. By understanding the fundamental mechanisms underpinning hypoxia-ischemia-induced serotonergic damage we will hopefully move closer to developing a successful clinical intervention to treat neonatal brain injury.

Figure 1

Schematic diagram depicting the major pathways involved in the synthesis, release, re-uptake and metabolism of serotonin in serotonergic neurons. Components of the figure have been modified from Motifolio. TpH: tryptophan hydroxylase; 5-HTP: 5-hydroxy-L-tryptophan; 5-HT: serotonin; SERT: serotonin transporter; MAO: monoamine oxidase; 5-HIAA: 5-hydroxyindoleacetic acid; 5-HTR: serotonergic receptor.