Fig. 12

Proposed model for the mechanisms involved in the impairment of motor coordination and learning and memory in rats with HE and for their improvement by infliximab. a Peripheral inflammation in PCS rats induces activation of microglia and astrocytes in the cerebellum leading to increased expression of the pro-inflammatory markers TNF-α and IL-1β. This neuroinflammation leads to enhanced membrane expression of GAT-3, a GABA transporter that in activated astrocytes reverses the transport direction, resulting in a release of GABA to the extracellular fluid leading to increased extracellular GABA in the cerebellum. The increase in GABA leads to motor in-coordination and to reduced ability to learn the Y maze task. b Treatment with infliximab reduces the peripheral inflammation which prevents the activation of microglia and astrocytes and the associated enhancement of TNF-α and IL-1β expression in the cerebellum. This leads to normalized membrane expression of GAT3 in the astrocytes while it increases the expression of GAT1 in Purkinje neurons facilitating GABA uptake from the extracellular space resulting in normalized extracellular GABA concentration. As a consequence, the motor coordination is improved and the learning ability in the Y maze is restored