Neonatal allopregnanolone levels alteration: effects on behavior and role of the hippocampus

Abstract

Several works have pointed out the importance of the neurosteroid allopregnanolone for the maturation of the central nervous system and for adult behavior. The alteration of neonatal allopregnanolone levels in the first weeks of life alters emotional adult behavior and sensory gating processes. Without ruling out brain structures, some of these behavioral alterations seem to be related to a different functioning of the hippocampus in adult age. We focus here on the different behavioral studies that have revealed the importance of neonatal allopregnanolone levels for the adult response to novel environmental stimuli, anxiety-related behaviors and processing of sensory inputs (prepulse inhibition). An increase in neonatal physiological allopregnanolone levels decreases anxiety and increases novelty responses in adult age, thus affecting the individual response to environmental cues. These effects are also accompanied by a decrease in prepulse inhibition, indicating alterations in sensory gating that have been related to that present in disorders, such as schizophrenia. Moreover, behavioral studies have shown that some of these effects are related to a different functioning of the dorsal hippocampus, as the behavioral effects (decrease in anxiety and locomotion or increase in prepulse inhibition) of intrahippocampal allopregnanolone infusions in adult age are not present in those subjects in whom neonatal allopregnanolone levels were altered. Recent data indicated that this hippocampal involvement may be related to alterations in the expression of gamma-aminobutyric-acid receptors containing α4 and δ subunits, molecular alterations that can persist into adult age and that can, in part, explain the reported behavioral disturbances.

Keywords: AlloP; Allopregnanolone; DHEA; Development; EMS; Emotional behavior; GABA; GABA(A)R; Hippocampus; KCC2; MAP2; NMDA; Neurosteroids; PN; PPI; Prepulse inhibition; THDOC; allopregnanolone; cotransporter K(+)–Cl(−) 2; dehydroepiandrosterone; early maternal separation; gamma amino-butyric acid; glutamate N-methyl-d-aspartate; microtubule-associated protein 2; postnatal day; prepulse inhibition; tetrahydrodeoxycorticosterone; type A gamma amino-butyric acid receptors.