dc.description.abstract | The hippocampus (HIP) is recognized as a major telencephalic area processing learning and
episodic memory events through the accumulation of neuronal signals deriving from the
different subregions. In particular, hippocampal neurons have received particular attention due
to some of their functional properties being regulated by GABAergic and Glutamat- (Glu)-ergic
neuronal signals during both postnatal and adult stages. For the present study, growth of
hamster hippocampal neurons on biohybrid membrane substrates allowed us to show for the
first time that the two major GABAA α receptor subunits (α2,5) promote early neuronal shaping
plus expression differences of the main neuronal cytoskeletal factors (GAP-43, MAP2, Syn, the
neurotrophin BDNF) along with Gluergic subtypes. In a first case, the selective GABAAR
agonist diazepam (DZP; α2,5) caused very great (p<0.001) increases of dendritic sprouting and
branching processes mainly at DIV3, while its effects continued to account even for great
(p<0.01) axonal length during the entire culture period. In addition, DZP also accounted for
great (p<0.01) up-regulation of neuritic NR1, GluR2 and MAP2 while it moderately (p<0.05)
increased synaptophysin (Syn) at DIV7. Such effects were abolished by its highly selective
antagonist flumazenil. The application of the inverse α5 agonist (RY-080) tended to strongly
suggest its specific role on the dendritic component via the inhibition of BDNF, as shown by a
reduction of dendritic length at DIV7 concomitantly to very low levels of the neurotrophin.
Conversely, the effects of the preferentially specific agonist for hippocampal α2 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 contextually to these morphological variations,
the transcription of some Gluergic receptor subtypes resulted to be altered. Indeed, the α2
agonist was responsible for a distinctly rising expression pattern of axonal NR1 mRNA levels
from DIV3 (p<0.01) until DIV7 (p<0.001), along with a very great up-regulation of Syn at
DIV7. In the case of RY-080, it evoked a very great (p<0.001) downregulation of dendritic
GluR2 at only DIV7. Together, our results demonstrate that GABAA α2,5 receptor-containing
subunits are considered key modulating neuronal elements of HIP morphological features by
regulating the precise synchronization of cytoskeletal factors. Moreover, the notable NR1 and
GluR2 transcription differences promoted by these GABAA α subunits tend to favorably
corroborate the early role of α2 + α5 on HIP neuronal networks in hibernating rodents through
the recruitment and activation of silent neurons. We are still at the beginning but further studies
are required to establish the nature of molecular signals controlling responses of the different
hippocampal subregions, which may have therapeutic bearings for neurological disorders. | en_US |