No abstract

The modulatory actions of GABA(A) 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 GABA(A) alpha receptor subunits (alpha(2,5)) 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 alpha(5) 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 alpha(2) 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 GABA(A) alpha(2,5) 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 GABA(A) alpha subunits tend to favorably corroborate the early role of alpha(2) + alpha(5) 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.

The isolation of the G-protein-coupled receptor 30 (GPR30), an orphan membrane receptor unrelated to nuclear estrogen receptors (ERs), has become a key factor towards the unraveling of rapid estrogen action. This membrane receptor together with cellular signaling intermediaries, i.e., extracellular signaldependent kinases 1 and 2, may promote neuronal proliferation and differentiation activities. In the present study, an evident gene expression pattern of GPR30 characterized postnatal 7 (young) and 60 (adult) days of age hamsters as shown by its heterogeneous mRNA distribution in hypothalamic, amygdalar and cerebellar areas of both sexes. In particular, most of the brain areas considered in the adult hamster plus only the amygdala and cerebellum of young animals behaved in a sexually dimorphic fashion. This similar pattern was also detected for the ERa and b, as shown by the latter receptor prevailing in young and adult females, while the former predominated in young females. Even for the two kinases, a sexually dimorphic distribution was featured above all for young hamsters. Overall, the findings of the present study established a distinct expression pattern of the novel ER (GPR30) that may operate differently in some brain areas of the hamster and this may provide interesting insights regarding its probable neuroprotective role during the execution of some hibernating states, which are typical of our rodent model.

It has now been established that a large number of man-made and natural chemicals are capable of interfering with the action of natural hormones. In this category "endocrine disruptors" such as the herbicide atrazine, when administered at ecological low doses (1 or 100 microg/kg per day) from gestational day 14 to postnatal day 21, provided a clear dimorphic neurodegenerative pattern in some brain areas of the domestic mouse (Mus musculus). Indeed, the high concentration (100 microg/kg per day) with respect to the low concentration (1 microg/kg per day) induced relevant neuronal damage in extrahypothalamic sites, such as the cortical and striatal areas in both sexes. Marked alterations in other areas, including the hippocampal and hypothalamic nuclei, were mostly typical of the female. At the neuronal level, the neuropeptide somatostatin, specific for the secretion of growth hormone, seemed to be a major target of atrazine effects, as demonstrated by evident subtype2,3,5 receptor mRNA differences of this neuropeptide, at least for the first two subtypes. In particular, a very strong (p < 0.001) upregulation of subtype2 expressing neurons was detected in female hypothalamic areas, specifically the suprachiasmatic nucleus, whereas a similar downregulatory trend was reported for some extrahypothalamic areas such as the striatum. Interestingly, very strong upregulatory and downregulatory actions were detected for neurons expressing subtype3 in male hypothalamic and amygdalar regions and in the cortical and hippocampal areas, respectively. Overall, it appears that these first neurotoxicological effects of atrazine are very likely linked to dimorphic expression patterns of specific somatostatin subtypes in discrete but key hypothalamic and extrahypothalamic areas of Mus musculus.

The neurotoxic 3-nitropropionic acid (3-NP), a freckled milk vetch-derived inhibitor of mitochondrial enzymatic processes that is capable of mimicking the typical pathological features of neurodegenerative disorders, behaved in a differentiated manner in a hibernating rodent (hamster) with respect to a nonhibernating rodent (rat). Treatment of the two rodents with both an acute and chronic 3-NP dose supplied deleterious neuronal effects due to distinct histamine receptor (H n R) transcriptional activities, especially in the case of the rat. In hamsters, these treatment modalities accounted for overall reduced global activity in a freely moving environment and overt motor symptoms such as hindlimb dystonia and clasping with respect to the greater abnormal motor behaviors in rats. This behavioral difference appeared to be strongly related to qualitative fewer neuronal alterations and, namely, lesser crenated cell membranes, swollen mitochondria, and darkened nuclei in hamster brain areas. Moreover, a mixed H 1,3 R mRNA expression pattern was reported for both rodents treated with a chronic 3-NP dose as demonstrated by predominantly low H 1 R mRNA levels (Ͼ50%) in rat striatum and cortex, whereas extremely high H 3 R levels (Ͼ80%) characterized the lateral and central amygdala nuclei plus the striatum of hamsters. Interestingly, the H 3 R antagonist (thioperamide) blocked 3-NP-dependent behaviors plus induced an up-regulation of H 1 R levels in mainly the above-reported hamster amygdalar nuclei. Overall, these results show, for the first time, that a major protective role against neurodegenerative events appears to be strongly related to the expression activity of H 1,3 R subtypes of amygdalar neurons in this hibernating model.