The effect of reactive Bergmann glia on short-term synaptic plasticity in cerebellar neurodegenerative models, caused by chronic activation of ChR2 and expression of the mutant ataxin-1

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Introduction. Synaptic plasticity is impaired in the early stages of a neurodegenerative process but is potentially reversible. The study of mechanisms associated with synaptic plasticity in neurodegenerative cerebellar conditions has enabled the search for potential therapeutic agents.

This study aimed to investigate the effect of the astrocytic link on paired-pulse facilitation (PPF) in cerebellar cortical synapses of mice, using a set of immunohistochemical, optogenetic, and electrophysiological analysis methods.

Materials and methods. Experiments were conducted on 12-week-old CD-1 mice. The model of murine cerebellar astrogliosis was created using chronic activation of light-sensitive ChR2 channels in Bergmann glia and after they expressed the mutant ataxin-1. To model astrocyte-mediated neurodegeneration, these mice were intracortically administered AVV GFAP-ChR2-mKate vector constructions with subsequent chronic 4-day light stimulation in vivo and LVV GFAP-ATXN1[Q85]-Flag without light stimulation. Mice in the control group were administered normal saline or LVV GFAP-ATXN1[Q2]-Flag. Changes in the PFF-excitatory postsynaptic currents in Purkinje cells were registered using the patch-clamp technique. Immunohistochemistry was used to examine anti-GFAP, mKate, and anti-ataxin-1 expression in the cerebellar cortex.

Results. For the reactive glia in the cerebellar cortex after chronic photostimulation, increased anti-GFAP immune reactivity and morphology changes in the form of process tortuosity were common. In Purkinje cell synapses with parallel fibers in these animals, the PPF coefficient was significantly increased because of impaired glutamate reuptake and presynaptic overexcitation with this neuromediator. However, photoactivation of reactive Bergmann glia led to a sharp slowing down of the glutamate-glutamine cycle and glutamate pool depletion in the presynapse, with a subsequent gradual reduction in the PPF coefficient. Such pathological mechanisms were found in the neurodegenerative model with selective damage to Bergmann glia by the mutant ataxin-1.

Conclusion. Astrocytes affect short-term synaptic plasticity such as PPF. In cerebellar astrogliosis, the PPF disturbance is multilevel: the high baseline level of PPF is significantly reduced after Bergmann glial activation, which is related to impaired glutamate reuptake by reactive glial cells.

About the authors

Аnton N. Shuvaev

Voyno-Yasenetsky Krasnoyarsk State Medical University ; Siberian Federal University

Author for correspondence.
Russian Federation, Krasnoyarsk

Оlga S. Belozor

Voyno-Yasenetsky Krasnoyarsk State Medical University

Russian Federation, Krasnoyarsk

Oleg I. Mozjei

Immanuel Kant Baltic Federal University

Russian Federation, Kaliningrad

Daria A. Yakovleva

Siberian Federal University

Russian Federation, Krasnoyarsk

Аndrey N. Shuvaev

Siberian Federal University

Russian Federation, Krasnoyarsk

Marina V. Smolnikova

Voyno-Yasenetsky Krasnoyarsk State Medical University; Research Institute of Medical Problems of the North, Federal Research Center Krasnoyarsk Science Center of the Siberian Branch of the Russian Academy of Sciences

Russian Federation, Krasnoyarsk

Еlena A. Pozhilenkova

Voyno-Yasenetsky Krasnoyarsk State Medical University

Russian Federation, Krasnoyarsk

S. . Каsparov

University of Bristol

United Kingdom, Bristol

Vladimir V. Salmin

Voyno-Yasenetsky Krasnoyarsk State Medical University

Russian Federation, Krasnoyarsk

Аlla B. Salmina

Voyno-Yasenetsky Krasnoyarsk State Medical University

Russian Federation, Krasnoyarsk


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Copyright (c) 2021 Shuvaev А.N., Belozor О.S., Mozjei O.I., Yakovleva D.A., Shuvaev А.N., Smolnikova M.V., Pozhilenkova Е.A., Каsparov S..., Salmin V.V., Salmina А.B.

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