Marti Mengual Ulisses, Wybo Willem A.M., Spierenburg Lotte J.E., Santello Mirko, Senn Walter, Nevian Thomas (2020), Efficient low-pass dendro-somatic coupling in the apical dendrite of layer 5 pyramidal neurons in the anterior cingulate cortex, in The Journal of Neuroscience
Romanos Jennifer, Benke Dietmar, Pietrobon Daniela, Zeilhofer Hanns Ulrich, Santello Mirko (2020), Astrocyte dysfunction increases cortical dendritic excitability and promotes cranial pain in familial migraine, in Science Advances
, 6(23), eaaz1584-eaaz1584.
Romanos Jennifer, Thieren Laetitia, Santello Mirko (2019), Diving into new depths of astrocyte signaling, in Nature Neuroscience
, 22(11), 1749-1750.
Pagani Martina, Albisetti Gioele W., Sivakumar Nandhini, Wildner Hendrik, Santello Mirko, Johannssen Helge C., Zeilhofer Hanns Ulrich (2019), How Gastrin-Releasing Peptide Opens the Spinal Gate for Itch, in Neuron
, 103(1), 102-117.e5.
Santello Mirko, Toni Nicolas, Volterra Andrea (2019), Astrocyte function from information processing to cognition and cognitive impairment, in Nature Neuroscience
, 22(2), 154-166.
Romanos Jennifer, Benke Dietmar, Saab Aiman, Zeilhofer Hanns Ulrich, Santello Mirko (2019), Differences in glutamate uptake between cortical regions impact neuronal NMDA receptor activation, in Communications Biology
Santello Mirko, Bisco Alberto, Nevian Natalie Elisabeth, Lacivita Enza, Leopoldo Marcello, Nevian Thomas (2017), The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain, in Neurobiology of Disease
, 106, 214-221.
Capuani Clizia, Melone Marcello, Tottene Angelita, Bragina Luca, Crivellaro Giovanna, Santello Mirko, Casari Giorgio, Conti Fiorenzo, Pietrobon Daniela (2016), Defective glutamate and K + clearance by cortical astrocytes in familial hemiplegic migraine type 2, in EMBO Molecular Medicine
, 8(8), 967-986.
Fruh S., Romanos J., Panzanelli P., Burgisser D., Tyagarajan S. K., Campbell K. P., Santello M., Fritschy J.-M. (2016), Neuronal Dystroglycan Is Necessary for Formation and Maintenance of Functional CCK-Positive Basket Cell Terminals on Pyramidal Cells, in Journal of Neuroscience
, 36(40), 10296-10313.
Background: Migraine is a severely debilitating disorder affecting a large fraction of the population and it has been classified as one of the 20 most disabling diseases. It is characterized by long-lasting pulsating unilateral headache often accompanied by a number of other neurological symptoms (aura). There is only limited knowledge on the mechanism underlying the occurrence of migraine attacks. The current hypothesis points for increased cortical excitability as the cause for migraine. Thus, in migraine patients sudden raise in brain activity triggers the so-called cortical spreading depression (CSD), a depolarizing wave that slowly travels through the cortex, which underlies aura and leads to transient activation of meningeal nociceptors. Yet, enhanced excitability of cortical areas responsible for pain perception may play a role in the establishment of the pathological condition. I could recently demonstrate that plasticity of specific dendritic channels in one of these areas (the anterior cingulate cortex, ACC) is at least partially responsible for neuropathic pain occurrence. Since migraine and chronic pain share many important features (spontaneous pain episodes, allodynia, hyperalgesia, etc.) and both pathologies are associated with recurrent activation of the cortical pain matrix my hypothesis is that they may be caused by similar mechanisms. Working hypothesis: I hypothesize that, in a mouse model of migraine caused by a mutation of a gene expressed by glial cells, neurons of the ACC display intrinsic hyperexcitability. Since glial cells can strongly influence activity of neurons, this mutation may engender secondary neuronal malfunction leading to ACC hyperexcitability. Altered activity of this brain area could be responsible for increased likelihood of episodic activation and sensitization of the trigeminovascular pain and implicated in migraine chronification.Aims and experimental design: Neuronal properties in the migraine mouse model will be assessed by double somatic and dendritic patch-clamp recordings in a brain slice preparation containing the ACC. Plasticity of glial cell function will be assessed by recording K+ and glutamate uptake currents in parallel with Na+ and glutamate imaging in situ. The inhibitory effect of agonists and antagonists of receptors for neuromodulators will be tested on ACC neurons by somatic and dendritic recordings in the slice and in vivo microinjections.Expected results and impact: If the ACC, a cortical region implicated in pain perception, displays altered neuronal activity, this will be the first report showing that abnormal cortical activity is not only responsible for spreading depression occurrence but it may additionally favor pain establishment and central sensitization. Characterization of these neuronal alterations and candidate receptors able to modulate neuron’s activity in the ACC will help to devise new and/or more targeted treatment strategies for migraine therapy.