**5. The role of microglial cells**

The activity of astrocytes and neurons can be modulated by microglia. The microglial cells are innate of the immune system, have phagocytic function and perform active surveillance of the brain parenchyma. In the absence of inflammatory stimuli,

they remain quiescent and have an aspect endowed with ramifications (resting phenotype). When an inflammatory stimulus occurs, they become reactive and acquire an ameboid aspect (active phenotype), migrating to the injured site, where they proliferate and produce neurotoxic and neurotrophic factors that control tissue damage and regeneration. In hepatic encephalopathy, molecules such as ammonia, glutamate, and some locally produced neuroactive steroids (neurosteroids) may trigger the transition from the resting phenotype to the active phenotype [11].

Neuroinflammation modulates glutamatergic activity. Studies have shown that microglial activation in the cerebellum of rats exposed to chronic hyperammonemia promotes an increase in the production of proinflammatory cytokines, such as TNFα and IL-1b, in addition to an increase in the expression of TNFα receptors. Of particular importance, TNFα receptors are also expressed on the surface of astrocytes and their stimulation induces increased glutaminase, contributing to the increase of glutamate synthesis [28]. There is also evidence that excess glutamate causes microglial activation, resulting in an intercellular vicious cycle [11].

Another important neurotransmission system affected by neuroinflammation includes a class of peripheral gamma-aminobutyric acid (GABA) receptor, known as translocator protein (TSPO), which is expressed in the outer mitochondrial membrane of neurons. Although poorly present under normal conditions, microglial activation strongly increases its concentration, which can be seen in cirrhotic patients through studies with positron emission tomography and carbon 11-labeled radiotracer that specifically bind to it [11]. It is known that TSPO mediates the synthesis of neurosteroids from cholesterol, and its increased expression provides an important link between neuroinflammation and increased GABAergic activity [12].

Like hyperammonemia, neuroinflammation is not sufficient to produce minimal hepatic encephalopathy: evidence of this is the fact that microglial proliferation can also be found in cirrhosis without encephalopathy, suggesting that it plays a role much more associated with neuroprotection than production of tissue damage [11]. Current knowledge supports the theory that there is the necessity of the coexistence of hyperammonemia and neuroinflammation, interacting synergistically, for the occurrence of neuropsychiatric disorders [10, 26]. In addition, at least one experimental study demonstrates that it is possible to produce cognitive deficits with the combination of these two factors, even in the absence of underlying liver disease [11].
