Optogenetic and chemogenetic modulation of astroglial secretory phenotype

Abstract

Astrocytes play a major role in brain function and alterations in astrocyte function that contribute to the pathogenesis of many brain disorders. The astrocytes are attractive cellular targets for neuroprotection and brain tissue regeneration. Development of novel approaches to monitor and to control astroglial function is of great importance for further progress in basic neurobiology and in clinical neurology, as well as psychiatry. Recently developed advanced optogenetic and chemogenetic techniques enable precise stimulation of astrocytes in vitro and in vivo, which can be achieved by the expression of light-sensitive channels and receptors, or by expression of receptors exclusively activated by designer drugs. Optogenetic stimulation of astrocytes leads to dramatic changes in intracellular calcium concentrations and causes the release of gliotransmitters. Optogenetic and chemogenetic protocols for astrocyte activation aid in extracting novel information regarding the function of brain’s neurovascular unit. This review summarizes current data obtained by this approach and discusses a potential mechanistic connection between astrocyte stimulation and changes in brain physiology.

Optogenetic Activation of Astrocytes—Effects on Neuronal Network Function

“…Astrocytes do not generate action potentials in response to a stimulus, but respond with intracellular increase of [Ca 2+ ] [7]. When Ca 2+ waves propagate in astrocyte cytoplasm, serine, cytokines, and lactate are released, which can modulate activity of neighboring neurons [8]. The ability of astrocytes to release glutamate allows regulation of the function of NMDA receptors, thereby controlling the excitation of neuronal network [9].…”

Genetic Constructs for the Control of Astrocytes’ Activity

“…The aberrant functioning of astroglia was observed in neurodevelopmental and neurodegenerative diseases, brain injury, and neuroinflammation. Given these observations, the modulation of astrocytes affects the progression of brain diseases and is considered a promising neuroprotective and neuroregenerative therapy [ 4 , 7 , 8 , 9 ]. However, targeted modulation of astroglial activity faces numerous problems.…”

“…Release of lactate from astrocytes results in the metabolic support of activated neurons due to rapid conversion into pyruvate and fueling the mitochondria respiration (astrocyte-neuron lactate shuttle) [ 30 , 31 ] as well as in the modulation of blood–brain barrier integrity or initiation of angiogenesis/barriergenesis [ 32 ]. Even though there are some controversial data on the lactate-driven communication of astrocytes and neuronal cells [ 33 ], this mechanism is considered as a target for manipulating the astroglial activity in vitro or in vivo [ 7 ].…”

“…It was shown that activation of astrocytes using either a chemogenetic or an optogenetic genetically encoded tool during learning resulted in memory recall enhancement on the following day, suggesting the involvement of glial cells in plasticity regulation [ 45 ]. Most contemporary approaches are optogenetics based on a range of tools involving expression in astrocytes of specific light-sensitive opsins [ 46 ] or chemogenetic approaches using artificial receptors in astroglial cells [ 7 ].…”

Novel Approaches Used to Examine and Control Neurogenesis in Parkinson′s Disease

“…As a result of activation, extracellular K+ concentrations transiently rise, astrocytes release gliotransmitters and change their mitochondrial activity and proliferative status [172][173][174]. Actually, this is a principle of optogenetic photostimulation of astroglial cells expressing ChR2 or optoGPCRs under the astroglial promoters (i.e., GFAP), which recently appeared as a new approach to control brain activity [175][176][177][178].…”