Cognitive Impairment Associated With Cortical and Hippocampal Microglia Activation and Altered Synaptic Function in a Rat Model of Chronic Hepatic Encephalopathy

Background: Hepatic encephalopathy (HE) is broadly defined as brain dysfunction caused by impaired liver function and/or portal-systemic shunting, which manifests as a wide range of neurocognitive and neuropsychiatric abnormalities ranging from subclinical alterations to coma. Under cirrhosis conditions, more than 80% of patients can develop HE and exhibit mild cognitive impairment which can be detected through psychometric tests or neurophysiological assessment. Several pathophysiological mechanisms are thought to underlie memory dysfunction in HE. However, the exact mechanisms remain not fully understood. Microglia activation and the subsequent neuroinflammation might be responsible for memory abnormalities observed in HE patients. Methods: The aims of the present investigation were to assess long term memory (LTM) and identify microglial changes and synaptic plasticity in a chronic model of HE (CHE). The study was carried out in male Wistar rats with chronic liver failure induced by thioacetamide (TAA. 100mg/kg. b.w) administration. LTM function was assessed by Morris water maze test (MWM), together with microglial marker Iba1 (for activation) within the hippocampal subfields and dentate gyrus (DG) and CD68+ staining in microglia as well as neuronal markers; beta III tubulin, synaptophysin, postsynaptic density protein 95 (PSD95) and tau protein. Results: Our data showed impaired LTM in our CHE rats with significant elevation of microglia activation in the CA1 region of the hippocampus. Additionally, we found hyperphosphorylated tau protein (p-tau) in both cortical and hippocampal neurons and microglia in CHE rats. Moreover, we found beta III tubulin (a specific marker of neurons) and CD68+ staining in microglia, but not Iba1 in neurons, suggesting the engulfment of neurons by microglia. We also found synaptophysin, postsynaptic density protein 95 (PSD95), synaptotagmin and other neuronal proteins in the microglia, along with decreased dendritic length and reduced number of dendritic spines, strongly suggests the possible alterations in neuroplasticity, which may contribute to the observed neurobehavioral abnormalities. Conclusions: Our results revealed impaired long-term memory in TCH induced by TAA administration in rat associated with microglia activation and altered synaptic function and neuronal dysfunction (see Figure 1).Figure 1.: Evaluation of long-term spatial memory through the Morris water maze task (MWM). A: Graphical representations of the average time spent the target quadrant zone (SW; the south-west) for the 6th day in the MWM in control and TAA groups. B: Plots show the heat map and path length of the animal’s center point in the 6th day test in MWM. Data are shown as group mean values ± S.E.M. **P < 0.01 TAA vs Control.