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Marcon, Iacopo (2016) The role of GABAergic interneurons and astrocytes in the mechanism of seizure generation and propagation. [Tesi di dottorato]

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Abstract (inglese)

Within the brain, inhibitory signals originating from different GABAergic interneurons play crucial roles in establishing proper neural circuit operations. GABAergic interneurons are also directly involved in multiple neurological disorders, including epilepsy. The inhibitory signal from these cells can, indeed, counteract seizures and pharmacological agents that strengthen GABAergic transmission represent powerful anticonvulsant drugs extensively used by epileptic patients. Among the diverse classes of interneurons, Parvalbumin-expressing (Pv) interneurons have been proposed to play a central role in seizure control. In both experimental epilepsy models and patients these interneurons have been observed to generate a feedforward inhibition that effectively opposes seizure spread. When Pv interneurons were artificially activated in vivo with optogenetic techniques, ongoing seizures were interrupted. However, studies in different experimental epilepsy models revealed that Pv interneurons may, under certain conditions, favor seizure generation. It is therefore highly debated whether an intense activity of Pv interneurons can ultimately result in a pro- or in an anti-convulsant action.
In my Doctorate thesis, I used a mouse brain slice model of focal epilepsy in which the epileptogenic focus can be identified and the role of Pv interneurons in the generation and in the propagation of seizure-like events accurately analyzed by a combination of optogenetic, electrophysiological and imaging techniques. I observed that a selective rhythmic activation of Pv interneurons at the focus failed to prevent seizure generation, and it rather contributed to prolong seizure duration by synchronizing the afterdischarges of the clonic phase. Moreover, this pattern of Pv interneuron activation induced in pyramidal neurons a post-inhibitory rebound spiking that enhances neuronal synchrony and promotes seizure generation. In contrast, a selective activation of Pv interneurons distant from the focus blocked seizure propagation and shortened seizure duration at the focus. I then revealed that the reduced seizure duration at the focus was a direct consequence of the propagation block which probably prevented newly generated afterdischarges to travel backwards to the original focus of seizure initiation. The functional dichotomy of Pv interneurons described in the thesis opens new perspectives to our understanding of how local inhibitory circuits govern generation and spread of focal epileptiform activities.
Given the wealth of evidence pointing at Pv interneurons as key players in epilepsy, their disfunction might also be at the basis of genetic epilepsies such as the severe myoclonic epilepsy of infancy (SMEI or Dravet syndrome), a rare epileptic encephalopathy characterized by an elevated mortality rate, early onset and seizures associated with elevated body temperature. SMEI is associated with a loss of function of the NaV 1.1 isoform of the sodium channel α−subunit. Recently, a mouse model of SMEI was generated by specific deletion of the SCN1A gene that codes for NaV 1.1. Importantly, in this model GABAergic interneurons, and in particular Pv interneurons, have been proposed to be specifically affected by the NaV 1.1 deletion, resulting in a reduced excitability of these cells that might leads to network disinhibition and possibly seizures. Therefore, in the framework of a broad characterization of synaptic and network activities in in vitro and in vivo models from NaV 1.1 heterozygous KO mice, I report here evidence that the propagation of focal epileptiform events in brain slices from NaV 1.1 KO mice is faster than in WT mice, hinting at a weakening of feedforward inhibition that restrains seizure spread, most likely deriving from Pv interneuron impaired excitability. Finally, as accumulating evidence supports a novel view of brain function where neurons intensively cooperate with astrocytes, I decided to investigate if a specific communication between GABAergic interneurons and astrocytes may exist. Indeed, neurotransmitters can elicit in astrocytes Ca2+ elevations that, in turn, trigger the release of neuroactive molecules, commonly known as gliotransmitters. However, whether and how GABA, the main inhibitory neurotransmitter, can evoke similar Ca2+ elevations in astrocytes and what is the functional outcome of these GABA-activated astrocytes are questions poorly addressed. These questions are particularly relevant in epilepsy, where we observe a massive GABAergic activity during seizure generation and propagation. To this aim, I found that in somatosensory and temporal cortex slices loaded with the Ca2+ indicator Fluo-4 AM, a large number of astrocytes in the layer 5 exhibited somatic Ca2+ rises in response to GABA or Baclofen (a specific GABAB receptor agonist). Patch-clamp recordings in the presence of TTX also revealed that GABAB activation triggered N-methyl-D-aspartate receptor- mediated slow inward currents (SICs) in principal neurons, suggesting that astrocytes in local circuits can convert an intense inhibitory input into a delayed excitatory output. These data support the presence of a dynamic, bidirectional signaling between GABAergic interneurons and astrocytes, which opens new perspectives for our understanding of the role of these different cell types in brain physiopathology.

Abstract (italiano)


I segnali inibitori generati da una grande varietà di interneuroni GABAergici hanno un ruolo cruciale nell’assicurare il corretto funzionamento dei circuiti neuronali nel cervello. Gli interneuroni GABAergici sono anche direttamente coinvolti in numerose patologie neurologiche, compresa l’epilessia. L’azione inibitoria di questi interneuroni è in grado di contrastare le crisi epilettiche, e, infatti, gli agenti farmacologici che rafforzano la trasmissione sinaptica GABAergica sono utilizzati come farmaci anticonvulsivanti per i pazienti epilettici. Tra le numerose classi di interneuroni GABAergici, gli interneuroni esprimenti Parvalbumina (Pv) sembrano giocare un ruolo fondamentale nel controllo delle crisi epilettiche. In modelli sperimentali di epilessia ed in pazienti umani è stato dimostrato che queste cellule generano un’inibizione a feedforward, che si oppone efficacemente alla propagazione delle crisi epilettiche. Quando gli interneuroni Pv sono stati attivati artificialmente in vivo con tecniche optogenetiche, le crisi in corso sono state rapidamente interrotte. Ciò nonostante, altri studi hanno dimostrato che gli interneuroni Pv possono, in determinate circostanze, favorire la generazione delle crisi epilettiche. Non è quindi chiaro se l’intensa attività di questo sottogruppo di interneuroni abbia un effetto pro - o anti - epilettico.
Nella mia tesi di dottorato ho usato un innovativo modello di epilessia focale in fettine cerebrali di topo, dove il sito di generazione delle scariche epilettiche (focus) può essere precisamente identificato, per studiare il ruolo degli interneuroni Pv nella generazione e nella propagazione delle scariche epilettiche attraverso tecniche di elettrofisiologia, optogenetica e imaging. Innanzitutto ho osservato che l’attivazione ritmica degli interneuroni Pv nella zona focale non è in grado di prevenire la generazione di una scarica epilettica, mentre ha invece contribuito a prolungare la durata della crisi attraverso la sincronizzazione degli afterdischarges, picchi di attività tipici della fase clonica. Inoltre, questo pattern di attivazione degli interneuroni Pv ha indotto nei neuroni piramidali un rebound spiking post – inibitorio che ha intensificato la sincronia della rete neuronale, facilitando così la generazione della crisi. Al contrario, l’attivazione degli interneuroni Pv nelle aree distanti dal focus ha bloccato con successo la propagazione della scarica epilettica e ha ridotto la durata della crisi nel focus. Ho poi dimostrato che la ridotta durata della crisi nell’area focale è una conseguenza diretta del blocco della propagazione che ha probabilmente impedito ai nuovi afterdischarges di viaggiare a ritroso verso il focus per mantenere l’attività epilettica. La dicotomia funzionale degli interneuroni Pv descritta in questa tesi apre nuove prospettive per comprendere come i circuiti inibitori locali governano la generazione e la propagazione dell’attività epilettica focale.
Vista la grande mole di dati esistenti che indicano gli interneuroni Pv come protagonisti centrali nell’epilessia, è possibile ipotizzare che disfunzioni a loro carico contribuiscano alla patogenesi di forme genetiche come l’epilessia mioclonica severa dell’infanzia (SMEI, detta anche sindrome di Dravet). Questa grave patologia neurologica è una rara forma di encefalopatia epilettica caratterizzata da esordio precoce, crisi epilettiche associate ad elevata temperatura corporea ed elevato tasso di mortalità. La SMEI è associata ad una mutazione che causa l’inattivazione di uno dei due alleli codificanti la subunità alfa del canale del sodio voltaggio-dipendente NaV 1.1. Recentemente, è stato generato un modello murino di SMEI che riproduce abbastanza bene il fenotipo umano della malattia. In questo modello, gli interneuroni Pv sembrano essere selettivamente affetti dalla delezione dei canali NaV 1.1, provocando in queste cellule una riduzione di eccitabilità che può portare alla disinibizione della rete neuronale e, eventualmente, alle crisi epilettiche. Alla luce di queste premesse, nell’ambito di un’estesa caratterizzazione dell’attività sinaptica e di network in modelli in vitro ed in vivo da topi eterozigoti per la delezione dei canali NaV 1.1, ho osservato che le scariche epilettiche si propagano più velocemente nelle fettine cerebrali provenienti da topi eterozigoti per la delezione rispetto ai topi selvatici di controllo. Questa evidenza suggerisce un indebolimento dell’inibizione a feedforward derivante probabilmente dalla ridotta eccitabilità degli interneuroni Pv. Infine, dato che negli ultimi anni si sta facendo strada con forza una visione del funzionamento del cervello dove i neuroni collaborano strettamente con gli astrociti, ho voluto capire se esiste una interazione specifica tra interneuroni GABAergici ed astrociti, e quali conseguenze questa interazione ha sull’attività neuronale. Infatti, i neurotrasmettitori sono in grado di stimolare risposte Ca2+ negli astrociti le quali, a loro volta, possono provocare il rilascio di molecole neuroattive, comunemente note come gliotrasmettitori. Tuttavia, mentre la comunicazione tra astrociti e neuroni eccitatori è ben caratterizzata, l’interazione con gli interneuroni inibitori è ancora largamente inesplorata. In particolare, questa interazione può essere molto rilevante nell’epilessia, dove osserviamo una massiccia attività GABAergica durante la generazione e la propagazione della scarica epilettica. A questo proposito, ho osservato che nelle fettine di corteccia somatosensoriale e temporale caricate con l’indicatore Ca2+ Fluo-4 AM, la maggior parte degli astrociti nello strato 5 ha mostrato aumenti di Ca2+ in risposta all’applicazione di GABA o di Baclofen (un agonista specifico del recettore metabotropico GABAB). Per verificare se gli astrociti attivati dal GABA possano rilasciare glutammato, ho effettuato registrazioni di patch-clamp da neuroni piramidali grazie alle quali ho potuto verificare che l’attivazione del recettore GABAB negli astrociti provocava correnti depolarizzanti lente (SIC) nei neuroni mediate da recettore NMDA. I risultati di questi esperimenti suggeriscono che gli astrociti possono convertire nei circuiti locali un forte input inibitorio in un output eccitatorio ritardato, e che evidentemente esiste una comunicazione bidirezionale tra astrociti e interneuroni GABAergici che apre nuove prospettive sul ruolo di queste cellule nella fisiopatologia cerebrale.

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Tipo di EPrint:Tesi di dottorato
Relatore:Carmignoto, Piergiorgio
Dottorato (corsi e scuole):Ciclo 28 > Scuole 28 > BIOSCIENZE E BIOTECNOLOGIE > NEUROBIOLOGIA
Data di deposito della tesi:12 Gennaio 2016
Anno di Pubblicazione:12 Gennaio 2016
Parole chiave (italiano / inglese):Epilessia, Interneuroni, Astrociti, Optogenetica, Elettrofisiologia, Inibizione/ Epilepsy, GABAergic Interneurons, Astrocytes, Patch-clamp, Optogenetics, Feedforward-inhibition, Calcium
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/09 Fisiologia
Struttura di riferimento:Dipartimenti > Dipartimento di Biologia
Codice ID:9031
Depositato il:18 Ott 2016 17:45
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