(a) general impact

Alexei Verkhratsky is an internationally recognised scholar in the field of cellular neurophysiology, best known for his contributions to our knowledge of the physiology and pathophysiology of neuroglia. He was one of the first to discover the specific expression of neurotransmitter receptors in astrocytes and their activation in situ by physiological stimulation. He demonstrated (with H. Kettenmann) matching patterns of neuronal and glial receptors in situ, thus providing the basis for the concept of active and reciprocal neuronal-glial communications. He demonstrated that these receptors are connected to Ca²⁺ signalling cascades, which led to the important concept of glial Ca²⁺ excitability. He found a close relationship between Ca²⁺ and Na⁺ dynamics in astroglia and developed the concept of Na⁺ as a specific signalling molecule controlling local homeostatic responses of astrocytes. These discoveries have made a major contribution to the development of a new doctrine of the fundamental role of neuroglia in brain function. Verkhratsky also contributed to the emerging field of neurogliopathology; he characterised astroglial atrophy in the context of neurodegenerative diseases and proposed astrodegeneration as an early, key pathogenetic step in neurodegeneration. In a series of highly cited conceptual reviews (e.g. [1; 2]) he outlined basic principles of glial physiology and pathophysiology, which significantly influenced this rapidly developing area of neuroscience.

(b) selected studies

Glial physiology. In 1990 Verkhratsky discovered functional expression of low- and high-threshold Ca²⁺ channels in oligodendroglial precursors [3], the earliest finding underlying the concept of electrical excitability of NG2-glia. Subsequently, Verkhratsky (with Kettenmann) demonstrated that Ca²⁺ signalling in glial cells forms the basis of their excitability. He was the first to demonstrate in situ functional expression of metabotropic purinoceptors linked to InsP₃-induced Ca²⁺ release in oligodendroglia [4] and in cerebellar Bergmann astrocytes [5]. Furthermore, he discovered NMDA receptors in astroglia, and demonstrated their synaptic activation [6]. He found a unique expression of highly ATP-sensitive P2X_1/5 receptors in cortical astrocytes [7]. He was the first to measure astroglial sodium signals in response to physiological stimulation in situ [8] and subsequently developed a new concept of astroglial Na⁺ signalling [9; 10]. This concept is closely associated with the idea of an astroglial cradle (developed with Nedergaard [11]), which regards perisynaptic glial processes as a multifunctional compartment that controls emergence, maturation, maintenance and demise of synapses in the central nervous system. In microglia he demonstrated the role of endoplasmic reticulum (ER) Ca²⁺ stores and Ca²⁺ influx in regulation of the release of cytokines from macrophages [12].

Glial pathophysiology. Verkhratsky has developed a new concept of astroglial atrophy and glial paralysis as key elements of neuropathology. First, in collaboration with Rodriguez, he discovered prominent inhibition of neurogenesis (linked to stem astroglia) in the triple transgenic animal model of Alzheimer's disease (AD) [13]. Subsequently he discovered morphological and functional evidence for astroglial degeneration in the early stages of AD that preceded the appearance of the typical neuronal histopathology of AD in animal models [14]; these observations gave been subsequently corroborated in experiments on astrocytes differentiated from pluripotent stem cells obtained from AD patients [15]. He demonstrated deficient astrogliosis (indicative of functional atrophy) in the brain regions most vulnerable to AD [16]; these deficits in astroglial protection can be associated with brain region-specific alterations of the Ca²⁺ signalling toolkit [17]. He also demonstrated recruitment of microglia in the early, pre-symptomatic stages of AD in an animal model [18], and found that environmental stimulation (enriched environment and physical stimulation) restored AD associated glial abnormalities [19]. 

Calcium signalling. Verkhratsky contributed to identifying mechanisms of ER Ca²⁺ release in neurones; he made a detailed characterisation of  caffeine-induced Ca²⁺  release in sensory neurones [20] and was the first to perform real-time measurements of intra-ER Ca²⁺ dynamics in neurones to demonstrate the graded nature of Ca²⁺ -induced Ca²⁺  release [21]. He revealed the role of purinoceptors in neurotransmission in central and peripheral neurones [22] and established links between activation of P2 receptors and Ca²⁺ signalling. In collaboration with Rothwell he identified the modulatory role of interleukin-1 in controlling hippocampal synaptic plasticity [23].

Brain ageing. In 1993 Verkhratsky performed the first recordings of Ca²⁺ currents in aged sensory neurones [24]. Subsequently, he has pioneered cytosolic Ca²⁺ recordings in aged neurones in situ, which has provided direct experimental support for several aspects of a “Ca²⁺ theory of ageing”. In recent years he has characterised ageing of neuroglia [25] and performed the first in depth investigation of age-dependent changes in the expression of astroglial functional markers, which demonstrated that in ageing astrocytes undergo both atrophy and hypertrophy in a region-specific manner, thus questioning the popular concept of ubiquitous age-dependent astrogliosis [26].

(c) International recognition

Verkhratsky is an elected member of the German National Academy of Sciences Leopoldina, a member of Academia Europaea (as well as Vice-President and chairman of the Academy’s Life Sciences Class), a foreign member of Real Academia Nacional de Farmacia, Spain; a foreign member of National Academy of Sciences of Poland and a Corresponding Member of Slovenian Academy of Sciences and Arts. He has been awarded several Honorary professorships in Turkey and China. He is editor in chief of Cell Calcium, deputy editor of Cell Death and Disease, and a member of the editorial boards of many journals. In 2007 he published the first ever Textbook on Glial Neurobiology, and in 2013 he published a handbook Glial Physiology and Pathophysiology, which has rapidly become the reference book in the field. Verkhratsky has authored 7 and edited 9 books and has been a Guest Editor for 31 special issues of many international journals. He has published more than 400 papers in peer-reviewed journals, which have been cited more than 25000 times (H-index 86, Scopus, January 2020).

References

1    Kettenmann H, Hanisch UK, Noda M, Verkhratsky A (2011) Physiology of microglia. Physiol Rev 91:461-553

2    Verkhratsky A, Nedergaard M (2018) Physiology of Astroglia. Physiol Rev 98:239-389

3    Verkhratsky AN, Trotter J, Kettenmann H (1990) Cultured glial precursor cells from mouse cortex express two types of calcium currents. Neurosci Lett 112:194-198

4    Kirischuk S, Scherer J, Kettenmann H, Verkhratsky A (1995) Activation of P2-purinoreceptors triggered Ca²⁺ release from InsP₃-sensitive internal stores in mammalian oligodendrocytes. J Physiol 483:41-57

5    Kirischuk S, Moller T, Voitenko N, Kettenmann H, Verkhratsky A (1995) ATP-induced cytoplasmic calcium mobilization in Bergmann glial cells. J Neurosci 15:7861-7871

6    Lalo U, Pankratov Y, Kirchhoff F, North RA, Verkhratsky A (2006) NMDA receptors mediate neuron-to-glia signaling in mouse cortical astrocytes. J Neurosci 26:2673-2683

7    Lalo U, Pankratov Y, Wichert SP, Rossner MJ, North RA, Kirchhoff F, Verkhratsky A (2008) P2X1 and P2X5 subunits form the functional P2X receptor in mouse cortical astrocytes. J Neurosci 28:5473-5480

8    Kirischuk S, Kettenmann H, Verkhratsky A (1997) Na⁺/Ca²⁺ exchanger modulates kainate-triggered Ca2+ signaling in Bergmann glial cells in situ. FASEB J 11:566-572

9    Kirischuk S, Parpura V, Verkhratsky A (2012) Sodium dynamics: another key to astroglial excitability? Trends Neurosci 35:497-506

10  Verkhratsky A, Untiet V, Rose CR (2019) Ionic signalling in astroglia beyond calcium. J Physiol

11  Verkhratsky A, Nedergaard M (2014) Astroglial cradle in the life of the synapse. Philos Trans R Soc Lond B Biol Sci 369:20130595

12  Brough D, Le Feuvre RA, Wheeler RD, Solovyova N, Hilfiker S, Rothwell NJ, Verkhratsky A (2003) Ca²⁺ stores and Ca²⁺ entry differentially contribute to the release of IL-1 b and IL-1 a from murine macrophages. J Immunol 170:3029-3036

13  Rodriguez JJ et al. (2008) Impaired adult neurogenesis in the dentate gyrus of a triple transgenic mouse model of Alzheimer's disease. PLoS One 3:e2935

14  Olabarria M, Noristani HN, Verkhratsky A, Rodriguez JJ (2010) Concomitant astroglial atrophy and astrogliosis in a triple transgenic animal model of Alzheimer's disease. Glia 58:831-838

15  Jones VC, Atkinson-Dell R, Verkhratsky A, Mohamet L (2017) Aberrant iPSC-derived human astrocytes in Alzheimer's disease. Cell Death Dis 8:e2696

16  Verkhratsky A, Marutle A, Rodriguez-Arellano JJ, Nordberg A (2015) Glial Asthenia and Functional Paralysis: A New Perspective on Neurodegeneration and Alzheimer's Disease. Neuroscientist 21:552-568

17  Grolla AA, Sim JA, Lim D, Rodriguez JJ, Genazzani AA, Verkhratsky A (2013) Amyloid-beta and Alzheimer's disease type pathology differentially affects the calcium signalling toolkit in astrocytes from different brain regions. Cell Death Dis 4:e623

18  Rodriguez JJ, Witton J, Olabarria M, Noristani HN, Verkhratsky A (2010) Increase in the density of resting microglia precedes neuritic plaque formation and microglial activation in a transgenic model of Alzheimer's disease. Cell Death Dis 1:e1

19  Rodriguez JJ, Noristani HN, Verkhratsky A (2015) Microglial response to Alzheimer's disease is differentially modulated by voluntary wheel running and enriched environments. Brain Struct Funct 220:941-953

20  Usachev Y, Shmigol A, Pronchuk N, Kostyuk P, Verkhratsky A (1993) Caffeine-induced calcium release from internal stores in cultured rat sensory neurons. Neuroscience 57:845-859

21  Solovyova N, Veselovsky N, Toescu EC, Verkhratsky A (2002) Ca²⁺ dynamics in the lumen of the endoplasmic reticulum in sensory neurons: direct visualization of Ca²⁺-induced Ca²⁺  release triggered by physiological Ca²⁺  entry. EMBO J 21:622-630

22  Pankratov Y, Lalo U, Krishtal O, Verkhratsky A (2002) Ionotropic P2X purinoreceptors mediate synaptic transmission in rat pyramidal neurones of layer II/III of somato-sensory cortex. J Physiol 542:529-536

23  Ross FM, Allan SM, Rothwell NJ, Verkhratsky A (2003) A dual role for interleukin-1 in LTP in mouse hippocampal slices. J Neuroimmunol 144:61-67

24  Kostyuk P, Pronchuk N, Savchenko A, Verkhratsky A (1993) Calcium currents in aged rat dorsal root ganglion neurones. J Physiol 461:467-483

25  Lalo U, Palygin O, North RA, Verkhratsky A, Pankratov Y (2011) Age-dependent remodelling of ionotropic signalling in cortical astroglia. Aging Cell 10:392-402

26  Rodriguez JJ, Yeh CY, Terzieva S, Olabarria M, Kulijewicz-Nawrot M, Verkhratsky A (2014) Complex and region-specific changes in astroglial markers in the aging brain. Neurobiol Aging 35:15-23