Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine

Abstract

Understanding how the hippocampus processes episodic memory information during neuropathological conditions is important for treatment and prevention applications. Previous data have shown that during chronic neuroinflammation the expression of the plasticity related behaviourally-induced immediate early gene Arc is altered within the CA3 and the dentate gyrus; both of these hippocampal regions show a pronounced increase in activated microglia. Low doses of memantine, a low to moderate affinity open channel uncompetitive N-Methyl-d-aspartate receptor antagonist, reduce neuroinflammation, return Arc expression to control levels and attenuate cognitive deficits induced by lipopolysaccharide. Here we investigate whether neuroinflammation affects the accuracy of information processing in the CA3 and CA1 hippocampal regions and if this is modified by memantine treatment. Using the immediate early gene-based brain-imaging method called cellular analysis of temporal activity by fluorescence in situ hybridization, it is possible to detect primary transcripts at the genomic alleles; this provides exceptional temporal and cellular resolution and facilitates the mapping of neuronal activity. Here, we use this method to compare the neuronal populations activated by two separate experiences in CA1 and CA3 and evaluate the accuracy of information processing during chronic neuroinflammation. Our results show that the CA3 pyramidal neuron activity is not stable between two exposures to the same environment context or two different contexts. CA1 networks, however, do not differ from control conditions. These data suggest that during chronic neuroinflammation, the CA3 networks show a disrupted ability to encode spatial information, and that CA1 neurons can work independently of CA3. Importantly, memantine treatment is able to partially normalize information processing in the hippocampus, suggesting that when given early during the development of the pathology memantine confers neuronal and cognitive protection while indirectly prevents pathological microglial activation.

Hippocampal granule cells opt for early retirement

“…For example, using essentially the identical procedures and environments used here and in Chawla et al (2005), Rosi et al (2009) found that, for both CA3 and CA1, X 2 /X 1 were very close to the expected values.…”

Tumor necrosis factor-α triggers a cytokine cascade yielding postoperative cognitive decline

“…2C) (P < 0.01). Microglia, the innate immune cells of the CNS, usually reside in the quiescent state; these cells are tightly regulated and, upon activation, release cytotoxic compounds that disrupt homeostatic processes and neuronal functions (24)(25)(26). Microglia are activated following surgery, changing their small cell bodies and thin, long, ramified pseudopodia into an amoeboid morphology, with enlargement of the cell body (features described as microgliosis).…”

Why mesial temporal lobe epilepsy with hippocampal sclerosis is progressive: Uncontrolled inflammation drives disease progression?

“…There are reports that neuroinflammation affects the accuracy of information processing in the CA3 and CA1 hippocampal regions. Memantine treatment, which indirectly prevents pathological microglial activation during the development of the pathology, has been shown to partially normalize information processing in the hippocampus, suggesting that modulation of neuroinflammation may improve the cognitive function of patients with TLE [100].…”