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Published on: February 26, 2018
Expression variations of chromogranin A and α1,2,4 GABA(A)Rs in discrete limbic and brainstem areas rescue
Ennio Avolio1, Rosa Maria Facciolo, Raffaella Alò
1Comparative Neuroanatomy Laboratory, University of Calabria, Ponte P. Bucci 4B, 87030 Arcavacata di Rende, Cosenza, Italy; Health Center srl, via Alimena 6, 87100 Cosenza, Italy; VA San Diego Healthcare System/Department of Medicine, University of California-San Diego, La Jolla, CA 92093-0838, USA.
Insights
Hibernation involves altered brain neurochemistry, with changes in chromogranin A (CgA) and GABA(A) receptors linked to neuronal health. These findings offer insights into potential cardiovascular rescue mechanisms for neurodegenerative disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Cardiovascular Research
Background:
- Hemodynamic dysfunction and altered brain neuronal mechanisms are implicated in dementia and sleep disorders.
- Chromogranin A (CgA) and GABA(A) receptors (GABA(A)Rs) are neuroactive proteins involved in neuronal function.
- Hibernation provides a unique model to study physiological adaptations and neuronal resilience.
Purpose of the Study:
- To investigate the cerebral expression of CgA and specific GABA(A)R subunits during different hibernating states in hamsters.
- To correlate neuronal damage and altered gene expression with hemodynamic changes during torpor and arousal.
- To explore the role of CgA in modulating neuronal activity and its potential cardiovascular protective effects.
Main Methods:
- Analysis of CgA and GABA(A)R subunit mRNA levels in specific brain nuclei (PVN, CeA, NTS, Pe) of hibernating hamsters.
- Comparison of gene expression patterns during hypotensive torpor (TORP) and hypertensive arousal (AROU) states.
- Pharmacological manipulation using catestatin to assess CgA's role in GABAergic neurotransmission.
Main Results:
- Elevated CgA and GABA(A)R α1, α4 mRNA levels in PVN, CeA, and NTS during TORP, correlating with neuronal damage.
- Lower CgA levels and increased α2-containing GABA(A)Rs in amygdala, hippocampus, and NTS during AROU.
- Increased α4-containing GABA(A)Rs in the periventricular hypothalamic nucleus (Pe) during AROU.
- Catestatin perfusion enhanced GABA-dependent inhibitory currents, suggesting CgA's inhibitory role.
Conclusions:
- Hibernation involves significant alterations in CgA and GABA(A)R expression in key brain regions.
- These molecular changes are associated with neuronal integrity and hemodynamic shifts during torpor and arousal.
- The findings highlight novel molecular switching events in the brain that may confer cardiovascular protective abilities against neurodegeneration.
Abstract:
Recent interferences of hemodynamic functions via modified brain neuronal mechanisms have proven to be major causes of dementia and sleeping disorders. In this work, cerebral expression differences of the neuroactive vesicular chromogranin A (CgA) and distinct α GABA(A)R subunits were detected in the facultative hibernating hamster. In particular, damaged neuronal fields of hypotensive torpor (TORP) state were correlated to elevated CgA and GABA(A)R α1, α4 mRNA levels in the paraventricular hypothalamic nucleus (PVN), central amygdalar nucleus (CeA) plus solitary tractus nucleus (NTS). Conversely, few neurodegeneration signals of hypertensive arousal (AROU) state, accounted for mostly lower CgA levels in the same areas. This state also provided increased α2-containing sites in amygdala, hippocampal and NTS neurons together with elevated α4-containing receptors in the periventricular hypothalamic nucleus (Pe). Interestingly in our hibernating model, CgA appeared to preferentially feature inhibitory neurosignals as indicated by preliminary perfusion of amygdalar sites with its highly specific antihypertensive derived peptide (catestatin) promoting GABA-dependent sIPSCs. Overall, evident neuronal damages plus altered expression capacities of CgA and α1-, α2-, α4-GABA(A)Rs in CeA, Pe, PVN as well as NTS during both hibernating states corroborate for the first time key molecular switching events guaranteeing useful cardiovascular rescuing abilities of neurodegenerative disorders.
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