Accuracy of hippocampal network activity is disrupted by neuroinflammation: rescue by memantine.
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.
Rosi
S
S
Brain and Spinal Injury Center, University of California, San Francisco, CA, USA. rosis@ptrehab.ucsf.edu
Ramirez-Amaya
V
V
Vazdarjanova
A
A
Esparza
E E
EE
Larkin
P B
PB
Fike
J R
JR
Wenk
G L
GL
Barnes
C A
CA
D000818:Animals; D001931:Brain Mapping / Q000379:methods; D002478:Cells, Cultured; D002908:Chronic Disease; D003598:Cytoskeletal Proteins / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical / Q000379:methods; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology / Q000627:therapeutic use*; D005106:Exploratory Behavior / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression; D017781:Genes, Immediate-Early; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D017404:In Situ Hybridization, Fluorescence; D008070:Lipopolysaccharides; D008297:Male; D008559:Memantine / Q000494:pharmacology / Q000627:therapeutic use*; D017628:Microglia / Q000187:drug effects; D009415:Nerve Net / Q000503:physiopathology; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D020078:Neurogenic Inflammation / Q000188:drug therapy / Q000503:physiopathology* / Q000523:psychology; D009474:Neurons / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors
D003598:Cytoskeletal Proteins; D018691:Excitatory Amino Acid Antagonists; D008070:Lipopolysaccharides; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; C092069:activity regulated cytoskeletal-associated protein; D008559:Memantine