c/o Complesso Biologico Interdipartimentale
Viale Giuseppe Colombo 3
Reciprocal interactions between astrocytes and neurons in brain physiology and pathology
Astrocytic glial cells are key players in the control of brain tissue homeostasis. Recent works have extended the role of astrocytes also to the fine modulation of synaptic transmission andinformation processing in the brain, once considered to be exclusively neuronal functions. By releasing gliotransmitters (glutamate, ATP, D-serine, cytokines) astrocytes can modulate synapses with different mechanisms both at pre and postsynaptic level. Our main goal is to clarify how astrocytes modulate neuronal network activity in physiological and pathological conditions. Astrocytes involvement in very early steps of different neurological disorders like Alzheimer’s disease, Parkinson’s disease and epilepsy is supported by growing evidence, opening new unexploited therapeutic strategies. Our recent results show the involvement of astrocytes at seizure generation, pointing them as a novel target to treat seizures.Right panel: confocal fluorescence image of astrocytes (green) in slice of temporal cortex.
Astrocytes favor seizure generation.
In brain slices we developed an experimental model that, by using local neuronal stimulation, has the unique advantage to evoke focal seizure like discharges from a known restricted site and at known timing (Losi et al 2010). New anticonvulsant molecules can be easily studied with this experimental approach as reproducible seizure like events can be repeatedly induced. This model makes also possible to study the early cellular events that take place in the area of ictal discharge generation (ictogenesis). Doing this we found that astrocyte are activated by neurons before the generation of seizure like events (Figure 1). Using different experimental approaches we revealed that astrocytic activation or inhibition in the focal area favors or impairs, respectively, the generation of seizure like events (Gomez-Gonzalo et al 2010). These data reveal the importance of astrocytes in ictogenesis and support the idea of targeting these glial cells to develop novel antiepileptic therapies.
Fast spiking GABAergic interneurons shape focal seizure propagation.
Parvalbumin fast-spiking (Pv-FS) interneurons represent the most abundant subclass of GABAergic cells. These cells' axons contact soma and proximal dendrites of principal cells to efficiently modulate their firing activity. Recent results of our group revealed that the inhibitory activity that opposes, and occasionally prevents, ictal discharge propagation in temporal and entorhinal cortices are mainly due to Pv-FS interneurons activity (Cammarota et al 2013). Our data also show that seizure like discharge propagation occurs in modular groups of principal neurons that coincides with a sudden impairment of local Pv-FS interneurons firing activity that leads to a dramatic inhibitory failure (Cammarota et al 2013).
We are characterizing the reciprocal interaction between GABAergic interneurons and astrocytes. In our laboratory we are using optogenetic tools like Channelrhodopsin-2 to selectively activate specific neuronal subclasses, like those expressing Pv or Som, to study their contribution to astrocytic activation and to epileptiform activity. The modulation of synaptic transmission by astrocytic activity is also under investigation in different experimental conditions.
Intracellular calcium imaging with fast laser scanning microscopy (single or two-photon excitation) and simultaneous patch-clamp or field-potential recordings on brain slices and in vivo.
Mariotti L, Losi G*, Lia A, Melone M, Chiavegato A, Gómez-Gonzalo M, Sessolo M, Bovetti S, Forli A, Zonta M, Requie LM, Marcon I, Pugliese A, Viollet C, Bettler B, Fellin T, Conti F, Carmignoto G. Interneuron-specific signaling evokes distictive somatostatin-mediated responses in adult cortical astrocytes. Nature Communications. 2018 Jan 8;9(1):82. doi: 10.1038/s41467-017-02642-6. * equal contribution.
Librizzi L, Losi G*, Marcon I, Sessolo M, Scalmani P, Carmignoto G, de Curtis M. Interneuronal Network Activity at the Onset of Seizure-Like Events in Entorhinal Cortex Slices. J Neurosci. 2017 Oct 25;37(43):10398-10407. doi: 10.1523/JNEUROSCI.3906-16.2017. Epub 2017 Sep 25. * equal contribution.
Losi G, Mariotti L, Sessolo M, Carmignoto G. New Tools to Study Astrocyte Ca2+ Signal Dynamics in Brain Networks In Vivo. Front Cell Neurosci. 2017 May 9;11:134. doi: 10.3389/fncel.2017.00134.
Mariotti L*, Losi G*, Sessolo M, Marcon I, Carmignoto G. The inhibitory neurotransmitter GABA evokes long-lasting Ca2+ oscillations in cortical astrocytes. Glia. 2016 Mar;64(3):363-73. doi: 10.1002/glia.22933. * equal contribution.
Sessolo M, Marcon I, Bovetti S, Losi G, Cammarota M, Ratto GM, Fellin T and Carmignoto G. Parvalbumin-positive inhibitory interneurons oppose propagation but favor generation of focal epileptiform activity. J Neuroscience, 2015 Jul 1;35(26):9544-57. doi: 10.1523/JNEUROSCI.5117-14.2015.
Losi G, Mariotti L, Carmignoto G. GABAergic interneuron to astrocyte signalling: a neglected form of cell communication in the brain. Philos Trans R Soc Lond B Biol Sci. 2014.Oct 19;369(1654):20130609. doi: 10.1098/rstb.2013.0609. Review.
Cammarota M*, Losi G*, Chiavegato A, Zonta M, Carmignoto G. Fast spiking interneuron control of seizure propagation in a cortical slice model of focal epilepsy. J Physiol. 2013 Feb 15;591(4):807-22. doi: 10.1113/jphysiol.2012.238154. * equal contribution.
Gómez-Gonzalo M*, Losi G*, Chiavegato A, Zonta M, Cammarota M, Brondi M, Vetri F, Uva L, Pozzan T, de Curtis M, Ratto GM, Carmignoto G. An excitatory loop with astrocytes contributes to drive neurons to seizure threshold. PLoS Biol. 2010 Apr 13;8(4):e1000352. * equal contribution.