<p>Epilepsy is comorbid with cognitive and psychiatric dysfunctions. This pathophysiology, associated with hippocampal synaptodendritic structural and functional changes, is exacerbated by prolonged seizures (status epilepticus; SE). We found a correlation between hippocampal dendritic loss and microgliosis after SE, along with hyperactivation of the classical complement pathway (C1q-C3). These paralleled increased seizure frequency and memory deficits in a rat model of SE and acquired epilepsy. C1q leads to C3 cleavage into biologically active fragments C3a and C3b. Evidence suggests that C1q and C3b contribute to synaptic stripping by microglia in the developing brain and neurodegenerative disorders. Thus, we hypothesized that SE-induced C3 activation may alter hippocampal synaptic protein levels thereby promoting memory deficits. </p> <p>To test the hypothesis, different groups of wild type (WT) or C3 deficient (C3KO) mice were injected with pilocarpine (350mg/kg) to induce SE or saline (controls): WT-C, WT-SE, C3KO-C, and C3KOSE. At two weeks after SE, mice were subjected to novel object recognition (NOR) to evaluate recognition memory, and Barnes maze (BM) to measure hippocampal-dependent spatial learning and memory. Following behavioral testing, mice were sacrificed and hippocampi collected at either 2 or 5 weeks after SE to measure changes in C3 protein levels and levels of synaptic proteins including PSD95, Vglut1, and Vgat. As a method of verifying our findings, we used a second model of pilocarpine-induced SE in male Sprague Dawley rats. Starting at 7 days after SE, rats were treated with cobra venom factor (CVF; 100ng/g, i.p.) or vehicle (veh) every third day. On days 14-15 rats were subjected to open field and NOR to measure anxiety and recognition memory. On day 16, rats were sacrificed and hippocampi collected for western blotting.</p> <p>WT and C3KO mice were able to reach stage 4.5-6 seizures after pilocarpine injections. In NOR trial 1, exploration time for both objects was similar in all groups (<i>p</i> > .05). In trial 2, WT-C and C3KO-C mice spent more time exploring the novel object than the familiar one (<i>p</i> < .05) while WT-SE mice explored both objects equally (<i>p</i> > .05). Interestingly, C3KO-SE mice spent more time with the novel object similar to controls (<i>p</i> > .05), suggesting that the deficit in object recognition memory induced by SE was attenuated in C3KO mice. Similarly, veh- and CVF-treated control rats spent more time exploring the novel object during trial 2 (<i>p</i> < .05). The veh-treated SE rats did not show significant preference for the novel object versus familiar (<i>p</i> > .05), whereas the CVF-treated SE rats explored the novel object significantly more than the familiar (p < .05). These findings support that C3 inhibition after SE prevents recognition memory deficits. Furthermore, there was a reduction in synaptic proteins PSD95 and Vgat in the SE-veh group compared to the C-veh group. This difference was not observed in the C-CVF and SE-CVF groups, suggesting that blocking C3 after SE is neuroprotective against hippocampal synaptic loss.</p> <p>Taken together, these findings are the first to show an association between C3 activation and hippocampal and cognitive deficits in two rodent models of SE and acquired TLE. We found that depletion of C3 is sufficient to attenuate SE-induced deficits in NOR-evaluated recognition memory and changes in the levels of an inhibitory synaptic protein. In conclusion, our data suggest that SE-induced complement C3 activation contributes to hippocampal synaptic remodeling and impairments in recognition memory, and that the complement C3 may be a potential therapeutic target for the memory comorbidities associated with SE. Future studies will determine the effect of C3 inhibition on spontaneous recurrent seizures, and whether C3-guided and microglial-dependent phagocytosis is an underlying mechanism for the SE-induced epileptogenic synaptic remodeling.</p>

The diploma thesis is focused on standardization of the neuropsychological test The Free and Cued Selective Reminding Test with Immediate Recall (FCSRT-IR), this test is a one of memory tests which contains phase with controlled learning. In the theoretical part it deals with aging and cognitive functions especially memory, further episodic memory test especially FCSRT-IR and its administration and benefits of this test against other episodic memory tests. In the practical part of this diploma thesis we report norms based on population in age 60 years and older (N= 362; range of age from 61 to 97), the norms are based on National Normative Study of Cognitive Determinants of Healthy Ageing which took place from 2012 to 2015 (IGA NT13145) and the author of this diploma thesis was a member of its team. In the second part of this thesis we deal with validation study which was conducted on population of people with dementia in Alzheimer's disease (N= 37; range of age from 61 to 88) comparing with healthy control group. In this validation study we confirmed that FCSRT-IR is a sensitive method for detection dementia in Alzheimer's disease. Keywords: Episodic memory, FCSRT-IR, controlled learning, norms, validation

We have recently established that aberrant alkylacylglycerophosphocholine metabolism results in the increased tissue concentration of platelet activating factors (PAFs) in the temporal cortex of Alzheimer Disease (AD) patients and in TgCRND8 mice over-expressing mutant human amyloid precursor protein. PAF lipids activate a G-protein coupled receptor (PAFR) reported to be expressed by microglia and subsets of neurons in rat. It is not known whether this same expression pattern is recapitulated in mice however, as the expression has only been inferred by use of pharmacological PAFR antagonists, many of which impact on both PAFR-dependent and PAFR-independent signalling pathways. PAFR plays a role in long term potentiation (LTP) induction in rats. PAFR has also been implicated in behavioural indices of spatial learning and memory in rats. Contradictory reports using mice provide ambiguity regarding the role of PAFR in LTP induction in mice. To assess whether PAFR is expressed in murine neurons, I localized PAFR mRNA in wild-type C57BL/6 mice using PAFR KO mice as a negative control. I further showed that the loss of PAFR did not impair learning and memory although this assessment must be considered preliminary as the behavioural test employed was not optimized to detect changes in learning and memory of C57BL/6 mice over time adequately.Finally, I showed that the loss of PAFR in TgCRND8 mouse model of AD had no impact upon Aβ plaque number. My observations suggest that PAFR is restricted to microglial-like cells in mouse hippocampus and as such, it may not play a role in learning and memory.

In the early twentieth century, Karl von Frisch performed seminal work on the organization of social behavior of honey bees. Much of his work involved training individual foragers to distant artificial feeders. Similar training methods have been used in research laboratories for the better part of a century, and these methods lend themselves well to advanced undergraduate biology classes in animal behavior. In recent years, students have used these methods in group projects to study color preference and time-memory. In this Technical Paper, we describe the basic steps of training honey bees to a distant feeder. We also provide alternative methods for answering specific types of questions that students in animal behavior classes might wish to address.

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京都大学 / 新制・論文博士 / 博士(医科学) / 乙第13503号 / 論医科博第9号 / 新制||医科||10(附属図書館) / (主査)教授 林 康紀, 教授 髙橋 良輔, 教授 井上 治久 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

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