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

Brain and Spinal Injury Center, University of California, San Francisco, CA, USA.
Brain (Impact Factor: 9.2). 07/2009; 132(Pt 9):2464-77. DOI: 10.1093/brain/awp148
Source: PubMed


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.

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    • "However, its mechanisms of action on relieving cognitive and behavioral symptoms are unclear. Animal research shows that memantine, at doses comparable to those given to patients, can improve cognitive functions in normal animals (Parsons et al., 1999, 2007; but see Creeley et al., 2006), animal models of Alzheimer's disease (Martinez-Coria et al., 2010; Minkeviciene et al., 2004), depression (Quan et al., 2011), ischemia (Chen et al., 1998), and neuroinflammation (Rosi et al., 2009). Acute treatment with memantine restored an experience-dependent "
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    ABSTRACT: Memantine, an uncompetitive N-methyl-D-aspartate receptor antagonist, is used for treatment of patients with Alzheimer's disease. The mechanisms of memantine in relieving cognitive and behavioral symptoms are unclear, and this study attempts to elucidate its action on network and synaptic functions of the hippocampus. The effects of memantine on electrographic activity and hippocampal long-term potentiation (LTP) were investigated in freely moving rats. Basal dendritic excitation on hippocampal CA1 pyramidal cells showed a robust LTP after theta-frequency primed bursts, and the LTP was higher after 5-10 mg/kg intraperitoneal (ip) memantine pretreatment, as compared with saline pretreatment. Injection of scopolamine (5 mg/kg ip) before memantine failed to block the LTP-enhancing effect of memantine. Memantine as compared with saline pretreatment did not affect the LTP after an afterdischarge induced by high-frequency (200-Hz) train stimulation. Memantine (5 or 10 mg/kg ip) significantly enhanced gamma oscillations in the hippocampal local field potentials of 40-100 Hz during walking and awake immobility. Memantine at 10 mg/kg ip, but not at 5 mg/kg ip, increased prepulse inhibition of the acoustic startle response, while both 5 and 10 mg/kg ip memantine enhanced the acoustic startle response as compared with saline-injected rats. These electrophysiological and behavioral effects of memantine are unique among N-methyl-D-aspartate receptor antagonists but are consistent with memantine's effects in improving cognitive and sensorimotor functions of Alzheimer's patients. Copyright © 2015 Elsevier Inc. All rights reserved.
    Neurobiology of Aging 06/2015; 462(9). DOI:10.1016/j.neurobiolaging.2015.05.017 · 5.01 Impact Factor
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    • "In addition, the probability that the same cells transcribed Arc in both epochs was significantly higher (P < 0.05) in all three hippocampal regions for both trained and na€ ıve rats in the no change conditions relative to the room change conditions, suggesting the same map was called up on successive T-maze exposures . This pattern of results is comparable to studies using separate environments (Guzowski et al., 1999; Vazdarjanova and Guzowski, 2004; Rosi et al., 2009; Hartzell et al., 2013). "
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    ABSTRACT: Response reversal learning is facilitated in many species, including humans, when competing responses occur in separate contexts. This suggests hippocampal maps may facilitate the acquisition of competing responses and is consistent with the hypothesis that contextual encoding permits rapid acquisition of new behaviors in similar environments. To test this hypothesis, the pattern of Arc expression was examined after rats completed a series of left/right response reversals in a T-maze. This reversal training occurred in the same room, two different rooms, or within a single room but with the maze enclosed in wall-length curtains of different configurations (i.e., black/white square or circle). Across CA1 and CA3, successive T-maze exposures in the same room recruited the same cells to repeatedly transcribe Arc, while a unique population of cells transcribed Arc in response to each of two different rooms as well as to the two unique curtain configurations in the same room. The interference from original learning that was evident on the first reversal in animals without a context switch was absent in groups that experienced changes in room or curtain configuration. However, only the use of unique rooms, and not changes in the curtained enclosure, facilitated learning across response reversals relative to the groups exposed to only one room. Thus, separate hippocampal maps appear to provide protection from the original learning interference but do not support improved reversals over trials. The present data suggest changes in heading direction input, rather than remapping, are the source of facilitation of reversal learning. © 2013 Wiley Periodicals, Inc.
    Hippocampus 04/2014; 24(4). DOI:10.1002/hipo.22233 · 4.16 Impact Factor
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    • "In addition, many microglia can be found intimately abutting neuronal somata and arbors (Wekerle, 2005), and glutamate receptors at such extrasynaptic positions preferentially contribute to excitotoxicity (Sattler et al., 2000). A role for EAAs in neurodegeneration during inflammation is evinced by the protective actions of glutamate receptor antagonists in many models of neuroinflammation (Espey et al., 1998; Mascarucci et al., 1998; Willard et al., 2000; Groom et al., 2003; Bossuet et al., 2004; Rosi et al., 2009). Beyond these experimental models, natural disease correlations also imply a link between neuroinflammation and excitotoxicity; AD, HIV encephalitis, multiple sclerosis, cerebral ischaemia, traumatic brain injury and ALS (amyotrophic lateral sclerosis) all have inflammation–excitotoxicity intersections. "
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    ABSTRACT: Proinflammatory stimuli evoke an export of glutamate from microglia that is sufficient to contribute to excitotoxicity in neighboring neurons. Because microglia also express various glutamate receptors themselves, we were interested in the potential feedback of glutamate on this system. Several agonists of metabotropic glutamate receptors (mGluR) were applied to primary rat microglia, and the export of glutamate into their culture medium was evoked by lipopolysaccharide (LPS). Agonists of group-II and -III mGluRs (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (ACPD) and L-(+)-2-amino-4-phosphonobutyric acid (L-AP4) were both capable of completely blocking the glutamate export without interfering with the production of nitric oxide; the group-I agonist trans-azetidine-2,4-dicarboxylic acid (tADA) was ineffective. Consistent with the possibility of feedback, inhibition of mGluRs by (R,S)-alpha-2-methyl-4sulphonophenylglycine (MSPG) potentiated glutamate export. As the group-II and -III mGluRs are coupled to Gαi-containing G-proteins and the inhibition of adenylate cyclase, we explored the role of cyclic AMP (cAMP) in this effect. Inhibition of cAMP-dependent protein kinase by H89 mimicked the effect of ACPD, and the mGluR agonist had its actions reversed by artificially sustaining cAMP through the phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX) or the cAMP mimetic dibutyryl-cAMP. These data indicate that mGluR activation attenuates a potentially neurotoxic export of glutamate from activated microglia and implicate cAMP as a contributor to this aspect of microglial actions.
    ASN Neuro 07/2012; 4(5). DOI:10.1042/AN20120044 · 4.02 Impact Factor
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