protein local synthesis in dendrite


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BSI summer lecture 06thJuly Friday
Dr. Shigetada Nakanishi


Role of glutamate transmisstion
1. brain function such as memory, learining , movement  perception and cognition
2. development, generation
3. neurotoxicity

Ionotropic receptors
AMPA/kainate receptor
rapid
NMDA receptor
Ca** permeable receptors
Metabotropic receptors (mGluRs)
G-rotein-coupled receptors

contrauctioon of a cDNA bank from brNA
in vitro mRNA synthesis
electrophysiological measurement in mRNA-injectied oocyte
cloning of a functional cDNA by repeated fractionation of a response-positive cDNA mixture

NMDAR1 NMDAR2A,2B,2C,2D
AMPA-selective(9)
GluR1,R2,R3,R4
Kainate-selective
FluR5,6,7-?
mGluR

NR1 expression in the hipocumpas
NR2 cortex and hippocampus
2C cereberal
Group1
mGluR1/5 IP3/Ca++  DHOPG/MPEP/Quisqualate postsynaptic
Group2 cGMP
Group3 cGMP

Selective expression of mGluR1 and mGluR2 in the cerebellum

photoreceptor
mGluR6はvisualでとても重要な役割をしている。
bipolar cellには、2つある。off and on bipolar cells。2つは、同じようにglutamateでphotoreceptorに入力するが、
結果は違うものになる。
mGllluR6KOmiceは、ON responseを機能不全にする。でも、off signal(暗くすると反応する細胞)には、全く関係ない。


OPTOKINETIC NYSTAGMUS
30:1の濃淡では、mGluR6KOmiceは、反応したが、2:1では、応答が起きなかった。
メカニズムは、
mGluR6 inhibits the TRAP cahnnel opening.

Direction-selective response of On-Off retinal ganglion cell
Asymmetry between input and output of starburst cell.
Starburst cellは、放射状に延びるしんけいさいぼうだが、他からの入力とbipolar cellに対する出力が偏っている。

mGluR2 is dominantly expressed in starburst cell.
they can eliminateed starburst cell.
In wild type, direction-selective responses happened. But starburst-eliminated cell doesn't have direction-selective response.
These data indicate that starburst cells are charged for the selectivity.
In the starburst cell elimination is crucial for eye moving velocity. right and left.

Decision-making experiment
3つまたの迷路で、1つのゴールには、普通の飯とちょっとの危険。もう一つの方は、たくさんの飯と、たくさんの危険。
どっちに行くかを調べる。

Function and dysfunction of the basal ganglia circuitry
reversible neruotransmission blocking (RNB) technique for cell type-specific, reversible lblockade of transmission.
pathway -specific expression of tTA using D-virus and I-viurs (promoter diffrence)
Doxicyclin is nothing, tetanus toxin comes up. with Doxi suppresses toxin.
tetanus toxine kills the neurons through VAMP2.
virus-mediated specific expression of tetanus toxin in the direct and indirect pathways.

caocain induces hyper locomotion through D-RNB.
Cocain-induced conditioned place preference.
Direct pathway is crucial for cacain induced neuron function.
reward-based and aversive learning

彼らは、Dopaminシグナルを調べている。
Dopaminは直接と間接経路がある。
直接は、LTP-D1SPにつながる。これは、striatumにある。あと、間接はLTD-D2Enkで、これは、ドーパミンがこれを阻害する。このシグナルが、globus pallidusを阻害して、SNr/VTAを阻害する。直接経路は、D1を直接活性化して、SNr/VTAを阻害する。どっちも同じ効果。
結果として、SNr/VTAはThalamus, verebral cortexを活性化する。よって、reward-based learning, drug addiction

counteractive 反作用の

biological significance of two pathwways in reward and aversive behavior.

1. Animals gain rewards correctly and effectively by distinguishing between assoiative and non-associatinve rewarding stimuli
2. Animals need to repidly memorize aversive to avoid aversive.


The basal gangalia netword
cerebral cortex ---working memory assosciative learining habit.

basal ganlia (nucleus accambens--hippocampus(spacial learning), amygdala, septium

 

 

05July2012 サマースクールでのErin schuman (マックスプランク)の講演のメモ。

 

500 differenct protein species per synapse
50 copyies in each protein
25000 proteins per synapse
104 synapses per cell
250000000 proteins per cell
additional 250000000 proteins in ath eaxon
t1/2=24hurs.
Every 24hrs need at
polyribosomes are persent in or at the bases of spipnes in postsynaptic neurons  harris and spacek  Levy and steward 1982.
BDNF kang and schuman, science 1995,1996

BDNF-induced poteintiation was blocked by anisomycin, showing local translation.
5 UTR myr dGFP 3'UTR (aCamKII)               Aakalu Neuron 2001
local translation
1. Kang and schuman 1996, BDNF
2. Martin 1998 LTF in Apysia
3.Huber 2000 M-GluR-dependent LTD
4. Campbell and holt...

A list of 15 dendritic m RNAs identified by in situ hybriddization. steward and schuman, neuron 2003
But prior stduies shows that not much overlap of mRNA. 3 group tried to looking the mRNA in dendrites but 3 group did not overlaped-mRNA.
2500 mRNA estimation
Many many mRNAS for synaptically-relevant proteins now identiried in the neuropil.
Dendritic axon is founded the shank mRNNA with fish method.

conclusion
2550 population of mRNAs that are present in the mature dendrites or axons of CA1 pyramidal neurons.
estimate htat  more than 50% of the mRNAs within a neuron can be detected outside of the cell body.
things to think about
many mRNAs for proteins associated with presynaptic function
mTNA for disease -related proteins
homogeneity vs. jeterpgeneity of cell types
local transilation may play a fundamental role in the supply and maintenance of protiens- not just for plasticity.

Identifying and visualizing newly sythesized proteins.
synaptic neuropil.
Labeling of newly synthesized protiens in vivo?
Ngo et al., Nature Chemical Biology, 2009

Hippocampal-Prefrontal synchrony in psychiatric disease models  Joshua Godon 9th/July/2012

psychiatric disease is related to hippocampus and prefrontal cortex.
HPC-PFC connectivity in psychiatric disease models.
22q11 model mice
recruited by anxiety
 schizophrenis 22q11 model mice
working memory was lower than normal one.
Df(16)A+/- mice are deficient in mPFC-dHPC coherence
vHPC silencing reduces dHPC-mPC cherence

dHPC-spatial memory(上の方)
entorhinal cortex
perirhinal cortex
thalamus
mPFC

vHPC--anxiety(したのほう)
amygdala
mPFC
BNST hypothalamus
ventral striatum


mPFC neuron fireing pattern
vary in neurons
mPFC neurons encode arm type in elevated plus maze

aversive arm
safe arm