Distinct α subunits of the GABAA receptor are responsible for early hippocampal silent neuron-related activities

Abstract

The modulatory actions of GABAA receptor subunits are crucial for morphological and transcriptional neuronal activities. In this study, growth of hamster hippocampal neurons on biohybrid membrane substrates allowed us to show for the first time that the two major GABAA a receptor subunits (a2,5) are capable of early neuronal shaping plus expression differences of some of the main neuronal cytoskeletal factors (GAP-43, the neurotrophin--BDNF) and of Gluergic subtypes. In a first case the inverse a5 agonist (RY-080) seemed to account for the reduction of dendritic length at DIV7, very likely via lower BDNF levels. Conversely, the effects of the preferentially specific agonist for hippocampal a2 subunit (flunitrazepam) were, instead, directed at the formation of growth cones at DIV3 in the presence of greatly (P > 0.01) diminished GAP-43 levels as displayed by strongly reduced axonal sprouting. It is interesting to note that concomitantly to these morphological variations, the transcription of some Gluergic receptor subtypes resulted to be altered. In particular, flunitrazepam was responsible for a distinctly rising expression of axonal NR1 mRNA levels from DIV3 (P > 0.01) until DIV7 (P > 0.001), whereas RY-080 evoked a very great (P > 0.001) downregulation of dendritic GluR2 at only DIV7. Together, our results demonstrate that GABAA a2,5 receptor-containing subunits by regulating the precise synchronization of cytoskeletal factors are considered key modulating neuronal elements of hippocampal morphological growth features. Moreover, the notable NR1 and GluR2 transcription differences promoted by these GABAA a subunits tend to favorably corroborate the early role of a2 1 a5 on hippocampal neuronal networks in hibernating rodents through the recruitment and activation of silent neurons, and this may provide useful insights regarding molecular neurodegenerative events. © 2009 Wiley-Liss, Inc.