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Prando, Valentina (2018) Neuroeffector coupling in the heart: determinants of function and survival of cardiac sympathetic neurons. [Ph.D. thesis]

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Abstract (english)

Rationale: The sympathetic branch of the autonomic nervous system (ANS) operates continuous control on the function and structure of cardiac cells (Bers et al., 2009). In basal conditions, neuronal input to sino-atrial node (SAN) cardiomyocytes (CM) is responsible for the fine regulation of heart rate (HR), and in parallel, it influences the balance between protein synthesis and degradation in working CMs, thus determining the resting cellular trophism (Zaglia et al., 2013). It is also commonly appreciated that sympathetic neurons (SNs) are rapidly activated upon strenuous exercise or emotional stresses characterizing the so-called ‘fight-or-flight’ response, resulting in the recruitment of maximal cardiac performance through positive inotropic and chronotropic effects (Li et al., 2000). While these general mechanisms of regulation of heart physiology are commonly recognized and have been thoroughly investigated in the last decades in both normal and disease conditions (Franzoso et al., 2016), the relationship between the fine anatomy of the myocardial neuronal network and its function, as well as the biophysics of the neuro-effector communication remain largely uncovered.
Purposes: In our initial studies, we used various imaging methods to investigate the morphological aspects of myocardial innervation. Our results demonstrate that the heart of most mammals, including humans, is highly innervated by SN processes, which distribute throughout the different heart regions with a conserved, specie-specific pattern, and display regular varicosities (i.e. active neurotransmitter release sites), which appear in close contact with the target CM membranes. Furthermore, ultrastructural analysis showed that such contacts have features similar to those described for the well-known neuromuscular junction (NMJ), which, remarkably, include the accumulation of mitochondria in the "presynaptic" varicosities (Slater, 2003; Levitan et al., 2015).
This data prompted us to study:
i) the biophysics of neuro-cardiac communication, which was addressed using both in vitro and in vivo models, with the aim to determine the role of direct intercellular contact in the dynamics of neuro-effector coupling;
ii) whether dysfunction in SN mitochondria, as addressed in a newly developed murine model of Optic Atrophy Factor-1 (Opa1) haploinsufficiency (TOH-Opa1+/-), may affect the neurogenic control of the heart.
Results: i) Dynamics of neuro-effector coupling at ‘cardiac sympathetic’ synapses.
The aim of this study has been to investigated the dynamics of SN/cardiomyocyte intercellular signaling communication, both by FRET-based imaging of cAMP in co-cultures, as a readout of cardiac β-AR activation, and in vivo, using optogenetics in transgenic mice with SN-specific expression of Channelrhodopsin-2. We demonstrate that SNs and cardiomyocytes interact at specific sites both in the human and rodent heart, and in co-cultures. Accordingly, neuronal activation elicited intracellular cAMP increases only in directly contacted myocytes and cell-cell coupling utilized a junctional extracellular signaling domain with elevated noradrenaline concentration. In the living mouse, optogenetic activation of cardiac SNs, innervating the sino-atrial node, resulted in the instantaneous chronotropic effect, which shortened the heartbeat interval with single beat precision. The dose of the β-blocker propranolol inhibiting the effect of photoactivation was much higher than that blocking circulating catecholamines, thus indicating that sympathetic neurotransmission in the heart occurs at locally elevated noradrenaline concentration. Our in vitro and in vivo data suggest that the control of cardiac function by SNs, thanks to the establishment of a specific intercellular junctional-site, relies on ‘quasi-synaptic' intercellular communication. The closely juxtaposed membranes of neurons and cardiomyocytes outline an extracellular signaling domain allowing activation of the β-ARs localized within the junctional space high with [NE]. The very small volume of such domain allows a single neuronal action potential to release a [NE] sufficient to trigger detectable cAMP increase in the coupled cardiomyocytes.
ii) Role of the mitochondrial protein Opa1 in the regulation of the cardiac SN physiology.
In the study of neuro-cardiac interactions described above, we were intrigued by the observation that mitochondria accumulated in SN varicosities, and specifically concentrated in the subspace of the presynaptic membrane. Neuronal mitochondria are fundamental for several cellular functions, including neuro-exocytosis, neurotransmitter reuptake and maintenance of neuronal process trophism, but their specific role in cardiac SNs is largely unexplored.
We thus sought to determine whether dysfunctional mitochondria would compromise the neurogenic control of the heart. To this aim, we exploited a murine model generated in our laboratory, characterized by the haploinsufficiency of Opa1 gene (Hoppins et al., 2007), selectively in SNs. Opa1 is a key protein implicated in mitochondrial dynamics, and its deficiency causes an inherited neurodegenerative disease characterized by retinal ganglion cell death known as Autosomal Dominant Optic Atrophy (ADOA), leading to visual loss. Interestingly, ADOA patients also display peripheral neuropathy and cardiac rhythm abnormalities (Spiegel et al., 2016) suggesting the hypothesis that dysfunctional mitochondria may affect not only central but also peripheral neurons, and remarkably, the autonomic neurons innervating the heart (Yu-Wai Man et al., 2016). To address this hypothesis, we focused on cardiac sympathetic innervation in both adult and aged Opa1 haploinsufficient mice (TOH-Opa1+/-) mice, which was studied using morphological and functional assays.
Our data demonstrated that Opa1 haploinsufficiency leads to a decrease in cSN density, which starts in the adulthood but it is also present during ageing. This is accompanied to alterations in cSN distribution patterning and morphology. Cardiac dysinnervation in TOH-Opa1+/- mice results in a significant decrease in heart rate variability and increased propensity to arrhythmias developments. Consistently, we detected decreased SN density in skin biopsies from ADOA patients, which progresses during ageing.
Thus we can conclude that the Opa1 is essential for cSN homeostasis and indicate that its haploinsufficiency leads to cSN degeneration. The cSN dysinnervation causes the dysfunction of the extrinsic control of cardiac rhythm. The mechanisms responsible for Opa1 haploinsufficiency-dependent cSN degeneration will be assessed in vitro, with a focus on the NGF signalling. To translate our findings to the human pathology, we will analyse SN phenotype in skin biopsies from ADOA patients.
Conclusions: Collectively, the data from these two projects, pose the bases for future studies aimed at defining whether a primary alteration in the SN-CM contact contribute to the pathogenesis of several cardiovascular disorders and at clarifying the molecular mechanisms whereby defective mitochondrial dynamics causes SN degeneration.

Abstract (italian)

Razionale: ll sistema nervoso simpatico, componente del sistema nervoso autonomo (ANS), opera un continuo controllo della funzione e sulla struttura delle cellule cardiache. In condizioni basali, l’input neuronale ai cardiomiociti (CMs) del nodo seno-atriale (SAN) è responsabile della regolazione della frequenza cardiaca (HR) e, in parallelo, influenza l'equilibrio tra la sintesi e la degradazione proteica nei CM di lavoro, determinando così il trofismo cellulare (Zaglia et al., 2013). È anche comunemente noto che i neuroni simpatici (SNs) si attivano rapidamente dopo l’ esercizio fisico o dopo stress emozionali che caratterizzano la cosiddetta risposta "fight-or-flight", con conseguente aumento delle prestazioni cardiache massime attraverso effetti inotropici e cronotropici positivi (Li et al., 2000). Mentre questi meccanismi generali di regolazione della fisiologia del cuore sono comunemente riconosciuti e sono stati accuratamente studiati negli ultimi decenni sia nelle condizioni normali che in quelle patologiche (Franzoso et al., 2016), il rapporto tra la fine organizzazione della rete neuronale nel miocardio e la sua funzione, così come la biofisica della comunicazione neuro-cardiaca rimane in gran parte non nota.
Scopo della tesi: Nei nostri studi iniziali, abbiamo utilizzato diversi metodi di imaging per indagare gli aspetti morfologici dell'innervazione del miocardio. I nostri risultati dimostrano che il cuore della maggior parte dei mammiferi, compresi gli esseri umani, è altamente innervato dalle fibre simpatiche, che si distribuiscono nelle varie regioni del cuore con un pattern ben conservato, specie-specifico e mostrano varicosità (ovvero siti di rilascio di neurotrasmettitori attivi) regolari a stretto contatto con le membrane dei CMs target. Inoltre, l'analisi ultrastrutturale ha dimostrato che tali contatti hanno caratteristiche simili a quelle descritte per la nota giunzione neuromuscolare (NMJ), che comprendono tra le altre, l'accumulo di mitocondri nelle varicosità "presinaptiche" (Slater, 2003; Levitan et al., 2015).
Questi dati ci hanno spinto a studiare:
i) la biofisica della comunicazione neurocardiaca, che è stata affrontata con modelli sia in vitro che in vivo, al fine di determinare il ruolo del contatto diretto intercellulare nelle dinamiche di accoppiamento neuro-cardiaco;
ii) se la disfunzione nei mitocondri che si trovano nei SNs, valutata in un modello murino recentemente sviluppato nel laboratorio del mio PhD aploinsufficiente per la proteina Opa1 (Optic Atrophy Factor-1) (TOH-Opa1+/-), possa influenzare il controllo neurogenico del cuore.
Risultati: i) Dinamiche dell'accoppiamento neuro-cardiaco a livello della “sinapsi cardiaca".
Lo scopo di questo studio è stato quello di indagare le dinamiche della comunicazione tra SN/cardiomiociti, sia mediante l'imaging di cAMP in tempo reale nei CMs in co-cultura che esprimono il sensore per la FRET Epac1, per analizzare le risposte dei CMs dopo l'attivazione dei SNs, e in vivo, utilizzando l’optogenetica in topi transgenici con espressione specifica di Channelrhodopsin-2 nei SNs. Abbiamo quindi dimostrato che i SN ed i cardiomiociti interagiscono in siti specifici sia nel cuore umano che nei roditori, sia in vitro nelle co-culture. In particolare, la depolarizzazione dei SNs ha causato un aumento del [cAMP] intracellulare che è stato rilevato solo nei CMs innervati, quindi la comunicazione tra CM e SN avviene in un dominio di segnalazione extracellulare con un’elevata concentrazione di noradrenalina ([NE]). Nel topo in vivo, l'attivazione, tramite l’optogenetica, dei SN cardiaci, che innervano il nodo seno-atriale, ha prodotto un istantaneo aumento della frequenza cardiaca, che ha accorciato l'intervallo tra due battiti con una precisione a singolo battito. La dose del β-bloccante propranololo, utilizzata per inibire l'effetto della fotoattivazione, era molto più alta di quella in grado di bloccare le catecolamine circolanti, indicando così che la neurotrasmissione simpatica nel cuore si verifica a concentrazioni localmente elevate di noradrenalina. I nostri dati in vitro e in vivo suggeriscono che il controllo della funzione cardiaca da parte dei SN, grazie alla creazione di uno specifico sito giunzionale intercellulare, si basa sulla comunicazione intercellulare "quasi-sinaptica". Le membrane strettamente affiancate dei neuroni e cardiomiociti delineano un dominio di segnalazione extracellulare che consente l'attivazione dei β-AR localizzati all'interno dello spazio giunzionale con elevate [NE]. Il volume ristretto di tale dominio consente a un singolo potenziale d'azione neuronale di rilasciare una [NE] sufficiente a innescare l'aumento di cAMP rilevabile nei cardiomiociti accoppiati.
ii) Ruolo della proteina mitocondriale Opa1 nella regolazione della fisiologia dei neuroni simpatici cardiaci.
Nello studio delle interazioni neuro-cardiache descritte in precedenza, siamo stati intrigati dall'osservazione che i mitocondri si accumulavano nelle varicosità dei SNs e specificamente si concentravano nello spazio attorno alla membrana presinaptica. I mitocondri nei neuroni sono fondamentali per molte funzioni cellulari, tra cui la neuro-esocitosi, il recupero del neurotrasmettitore ed il mantenimento del trofismo del processo neuronale, ma il loro ruolo specifico nei SN cardiaci è in gran parte inesplorato. Abbiamo quindi cercato di determinare se mitocondri disfunzionali compromettessero il controllo neurogenico del cuore. A questo scopo, abbiamo sfruttato un modello murino generato nel nostro laboratorio, caratterizzato dall’ aploinsufficienza del gene che codifica per la proteina Optic Atrophy Factor-1 (Opa1) (Hoppins et al., 2007), selettivamente nei SNs. Opa1 è una proteina chiave implicata nelle dinamiche mitocondriali e la sua carenza causa una malattia neurodegenerativa ereditaria caratterizzata dalla morte delle cellule ganglionari retiniche, nota come Atrofia ottica autosomica dominante (ADOA), con conseguente perdita visiva. È interessante notare che i pazienti affetti da ADOA presentano anche neuropatia periferica e anomalie del ritmo cardiaco (Spiegel et al., 2016), suggerendo l'ipotesi che i mitocondri disfunzionali possono influenzare non solo i neuroni centrali ma anche periferici e, in modo notevole, i neuroni autonomici che innervano il cuore (Yu-Wai Man et al., 2016). Per indagare questa ipotesi, ci siamo concentrati sull'innervazione simpatica cardiaca sia nei topi aploinsufficienti per Opa1 (TOH-Opa1+/-) adulti che vecchi, utilizzando saggi morfologici e funzionali. I nostri dati hanno dimostrato che l'aploinsufficienza di Opa1 porta ad una diminuzione della densità di SN cardiaci, che inizia nell'età adulta ma è anche presente durante l'invecchiamento. Questo è accompagnato da alterazioni nella morfologia e della distribuzione dei SN. La disinnervazione cardiaca nei topi TOH-Opa1+/- determina una significativa riduzione della variabilità della frequenza cardiaca e una maggiore propensione allo sviluppo di aritmie. Coerentemente, abbiamo rilevato una diminuzione della densità dei SN nelle biopsie cutanee ottenute da pazienti con ADOA, che progredisce durante l'invecchiamento. Quindi possiamo concludere che Opa1 è essenziale per l'omeostasi dei SN e indica che la sua aploinsufficienza porta alla loro degenerazione. Tale disinnervazione inoltre causa la disfunzione del controllo estrinseco del ritmo cardiaco. I meccanismi responsabili della degenerazione dei SN aploinsufficienti per Opa1 verranno valutati in vitro, con un focus sulla segnalazione mediata dall’ NGF. Per tradurre i nostri risultati nella patologia umana, analizzeremo il fenotipo dei SN nelle biopsie cutanee ottenute dai pazienti con ADOA.
Conclusioni: Complessivamente, i dati di questi due progetti forniscono le basi per studi futuri finalizzati a definire se un' alterazione primaria nel contatto tra SN-CM contribuisca alla patogenesi di diversi disturbi cardiovascolari e al chiarimento dei meccanismi molecolari in cui un difetto nelle dinamiche mitocondriali possa provocare la degenerazione dei neuroni simpatici che innervano il cuore.

EPrint type:Ph.D. thesis
Tutor:Mongillo, Marco
Supervisor:Zaglia , Tania
Ph.D. course:Ciclo 30 > Corsi 30 > SCIENZE BIOMEDICHE SPERIMENTALI
Data di deposito della tesi:12 January 2018
Anno di Pubblicazione:2018
Key Words:Sympathetic neurons; Opa1; mitochondria; neuro-cardiac junction
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/46 Scienze tecniche di medicina di laboratorio
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche
Codice ID:10690
Depositato il:14 Nov 2018 13:22
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