Glial physiology

In 1990, Verkhratsky discovered functional expression of low- and high-threshold Ca²⁺ channels in oligodendroglial precursors, this is the earliest finding underlying the concept of electrical excitability of NG2-glia.^[11] When working in Berlin at the Max Delbruck Center for Molecular medicine Verkhratsky Verkhratsky and Kettenmann performed numerous seminal observation of intracellular Ca²⁺ signalling and defined the concept of glial Ca²⁺ excitability.^[12] He was the first to demonstrate in situ functional expression of metabotropic purinoceptors linked to InsP₃-induced Ca²⁺ release in oligodendroglia^[13] and in cerebellar Bergmann astrocytes.^[14]

After moving to Manchester, Verkhratsky focused on astroglia and characterised various aspects of astrocyte membrane physiology and regulation of glial [Ca²⁺]_i dynamics. In particular, he discovered functional NMDA receptors in cortical astroglia, and demonstrated their synaptic activation^[15] and contribution to astrocytic Ca2+ signalling triggered by neuronal activity. Subsequently, he identified a unique expression of highly ATP-sensitive P2X_1/5 receptors in cortical astrocytes and characterised their role in translating neuronal synaptic activity to astroglial [Ca²⁺]_i signalling.^[16]

Verkhratsky further extended the concept of astroglial excitability as "ionic" excitability mediated by major ions, which create ionic signals coordinated in space and time; these ionic signals control the activity of astroglial homeostatic cascades and link neuronal firing and synaptic transmission to astrocyte functional responses.^[17] The development of this concept begun from the very first recordings of astroglial Na⁺ signals in response to physiological stimulation in situ in cerebellar Bergmann radial astrocytes.^[18] Subsequently, Verkhratsky analysed astroglial Na⁺ dynamics associated with the activity of glial glutamate transporters that are critical for glutamate clearance and glutamatergic transmission.^[19] Verkhratsky found that activation of glial transporters either by exogenous glutamate or by activation of glutamatergic transmission results in large Na⁺ influx which generate substantial and long-lasting [Na+]_i transients in processes of astrocytes. Based on these observations, he proposed a new concept astroglial Na⁺ signalling.^[20] The concept of astroglial ionic excitability was further integrated in the theory of homeostatic astroglia^[21] and is closely associated with the definition of an astroglial cradle, developed with Maiken Nedergaard,^[22] that assigns to perisynaptic astrocytic processes a role of multifunctional compartment, which controls emergence, maturation, maintenance, performance and demise of synapses in the central nervous system. In a series of highly cited conceptual reviews he outlined basic principles of glial physiology and pathophysiology, which significantly influenced this rapidly developing area of neuroscience. Working with Arthur Butt, Verkhratsky published two textbooks on physiology and pathophysiology of neuroglia in 2007 and 2013 and have been the only didactic writings on neuroglia.

Cellular mechanisms of brain ageing

Verkhratsky conducted the first recordings of Ca²⁺ currents in aged sensory neurones in 1993.^[23] He subsequently pioneered cytosolic Ca²⁺ recordings in aged neurones in situ, which gave direct experimental support for multiple aspects of a "Ca²⁺ theory of ageing". Verkhratsky was the first to perform an in depth analysis of astrocytic structure and function in the ageing brain. He has demonstrated regional differences in astroglial morphological appearances, which ranged from cytoskeleton hypertrophy to cytoskeleton atrophy. He also found that large populations of astrocytes negative to classical marker GFAP but positive to glutamine synthetase or S100B protein do not show hypertrophic changes in the aged brain thus suggesting that brain senescence is not associated with widespread astrogliosis.^[24] He also performed first detailed analysis of functional properties of glutamate transporters, glutamate and purinoceptors in old astrocytes in situ and found that brain ageing is associated with significant decrease in the density of these signalling molecules.^[25]

Glial pathophysiology

Verkhratsky has developed a new concept of astroglial atrophy associated with the loss of function and glial paralysis as key elements of neuropathology; astroglial atrophy contributes to pathophysiology of several neurological diseases from neuropsychiatric disorders to neurodegeneration. First, in collaboration with Rodriguez, he discovered prominent inhibition of neurogenesis (linked to the radial astrocytes-neural stem cells) in the animal model of Alzheimer's disease.^[26] Subsequently, he discovered morphological and functional evidence for astroglial atrophy at the early stages of AD that preceded the appearance of the typical neuronal histopathology in animal models;^[27] these observations have been subsequently corroborated in experiments on astrocytes differentiated from pluripotent stem cells obtained from patients with clinically confirmed Alzheimer's disease in both familial and sporadic forms.^[28] He demonstrated deficient astrogliosis (indicative of functional atrophy) in the brain regions most vulnerable to Alzheimer-like pathology;^[29] these deficits in astroglial protection can be associated with brain region-specific alterations of the Ca²⁺ signalling toolkit. He also found that environmental stimulation (enriched environment and physical stimulation) restored AD associated glial abnormalities.^[30]

Physiology of neurones

Verkhratsky contributed to the identification of ER Ca²⁺ release mechanisms in neurones; he characterised in detail the caffeine-induced Ca²⁺ release in sensory neurones^[31] 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.^[32] Together with Denis Burdakov, he also found and characterised the link between physiological glucose changes and excitability of hypothalamic neurones.^[33]