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2015 Fiscal Year Research-status Report

Identification of neuron-glia signaling mechanisms required for synaptic plasticity and memory formation

Research Project

Project/Area Number 15K06729
Research InstitutionTokyo Metropolitan Institute of Medical Science

Principal Investigator

堀内 純二郎  公益財団法人東京都医学総合研究所, 認知症・高次脳機能研究分野, 主席研究員 (80392364)

Project Period (FY) 2015-04-01 – 2018-03-31
Keywords加齢性記憶障害 / グリア細胞 / ショウジョウバエ / 長期記憶
Outline of Annual Research Achievements

We are studying the causes of age-related memory impairment (AMI) using Drosophila as a model organism. Previously, we showed that aging affects two types of memory in flies, a short lasting form that can be measured 1 hr after a single training session, and protein synthesis-dependent long-term memory, which can be measured 24 hrs after multiple training sessions. We found that both of these memory defects are caused by age-related dysfunction of glial activity, and are currently identifying the mechanisms through which this occurs.

Defects in 1 hr memory are caused by an age-dependent decrease in production of a neuromodulator, D-serine. Memory and other brain functions require neuronal signaling, which, in turn, requires activity of neurotransmitters and neuromodulators. The neuromodulator, D-serine, is produced by glial cells, and is required for NMDA-type glutamate receptor signaling. We have found that D-serine amounts decrease upon aging, and artificially increasing amounts of D-serine prevents age-associated reductions in 1 hr memory. We show that old glial cells produce increased amounts of a protein, pyruvate carboxylase, which inhibits D-serine production. Thus, we find that we can improve 1 hr memory in old flies by either inhibiting pyruvate carboxylase activity or increasing D-serine amounts.

We are currently elucidating mechanisms causing decreased long-term memory in old flies.

Current Status of Research Progress
Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

To determine why aging causes decreases in long-term memory (LTM), we first examined the function of glia in LTM formation in young flies. We found that LTM is associated with increased glial transcription and protein synthesis. Furthermore, we found that these increases are required for LTM formation. While increases in transcription and translation in neurons have been known to be important for LTM, this is the first indication that LTM also requires changes in glial transcription/translation. We are currently characterizing this requirement.

Thus far, we have identified a glial transcription factor, Repo, whose activity is required for LTM, and increases during LTM formation. In addition, we have identified dEAAT1, a factor regulated by Repo that is also required for LTM. dEAAT1 functions as a glutamate transporter, decreasing glutamate signaling at synapses, suggesting that decreased neuronal activity is required for consolidation of memory into LTM.

To determine how aging affects LTM, we are currently examining how aging affects training-dependent increases in Repo and dEAAT1. We have preminary data suggesting that old flies express less Repo and dEAAT1 compared to young flies. Furthermore, we have obtained supporting data suggesting that artificially increasing expression of Repo and dEAAT1 in old glial cells prevents age-related impairments in LTM.

Strategy for Future Research Activity

We propose that age-related impairments in 1 hr memory and LTM are caused by impaired glial activity. Defects in 1 hr memory occur because old glial cells are unable to produce sufficient amounts of D-serine leading to decreased neuronal activity during memory acquisition. Defects in LTM are caused because old glial cells are unable to inhibit neuronal activity to memory consolidation, because they are unable to produce sufficient amounts of dEAAT1. We have three future goals. 1) We will demonstrate that training-dependent glial transcription is defective in old flies. 2) We will determine how neurons and glia communicate to regulate glial production of D-serine and dEAAT1 during memory formation. 3) We will determine the physiological consequences of decreased training-dependent glial expression in old flies.

1) We will measure training-dependent increases in transcription in young and old flies. We hypothesize that training-dependent increases in CREB-dependent neuronal transcription may not be affected by aging, while Repo-dependent increases in glial transcription will be reduced. 2) To identify neuronal/glial signaling processes, we will use both forward and reverse genetic screening strategies to identify neuronal and glial genes required for training-dependent increases in Repo activity. 3) To identify the physiological consequences of decreased Repo and dEAAT1 expression in old flies, we will determine the requirements of Repo and dEAAT1 in physiological processes such as sleep and neuronal viability during memory consolidation.

Causes of Carryover

I intended to attend an international meeting at Cold Spring Harbor Laboratory, New York in the United States in September 2015, but could not attend for health reasons. The 300,513 yen remaining from my 2015 budget is because I missed this meeting.

Expenditure Plan for Carryover Budget

Since I was unable to attend the Cold Spring Harbor meeting last year, I will instead attend the Society for Neuroscience meeting at San Diego, USA in 2016. I will use my remaining budget from 2015 to attend this meeting.

  • Research Products

    (4 results)

All 2015

All Journal Article (1 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 1 results,  Acknowledgement Compliant: 1 results) Presentation (3 results) (of which Int'l Joint Research: 1 results,  Invited: 3 results)

  • [Journal Article] Long-term memory formation in Drosophila requires training-dependent glial transcription2015

    • Author(s)
      Matsuno, M., Horiuchi, J., Yuasa, Y., Ofusa, K., Miyashita, T., Masuda, T., Saitoe, M.
    • Journal Title

      J. Neurosci

      Volume: 35 Pages: 5557-5565

    • DOI

      10.1523/JNEUROSCI.3865-14.2015

    • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
  • [Presentation] Glial activity and age-related memory loss in Drosophila2015

    • Author(s)
      Horiuchi, J.
    • Organizer
      Tohoku University Forum for Creativity: Symposium on Memory and Mind
    • Place of Presentation
      Tohoku University, Sendai, Miyagi
    • Year and Date
      2015-09-27 – 2015-09-30
    • Int'l Joint Research / Invited
  • [Presentation] Reduced glial activity causes age-related memory impairment in Drosophila2015

    • Author(s)
      Horiuchi, J.
    • Organizer
      The 8th Annual Symphony Symposium
    • Place of Presentation
      Hotel Metropolitan Edmont Tokyo, Chiyoda, Tokyo
    • Year and Date
      2015-09-26 – 2015-09-27
    • Invited
  • [Presentation] Learning and Memory in Fruitflies2015

    • Author(s)
      Horiuchi, J.
    • Organizer
      Invited lecture at Yokohama City University
    • Place of Presentation
      Yokohama City University, Yokohama, Kanagawa
    • Year and Date
      2015-07-31 – 2015-07-31
    • Invited

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Published: 2017-01-06  

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