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SUMMARY:Inhibition and adaptationin the outer retina - Intiguing synaptic 
 mechanisms with unexpected molecular players - Maarten Kamermans\, Netherl
 ands Institute for Neuroscience
DTSTART:20141020T153000Z
DTEND:20141020T170000Z
UID:TALK55216@talks.cam.ac.uk
CONTACT:P.H. Marchington
DESCRIPTION:Kamermans\, K. & Fahrenfort I. 2004. Ephaptic interactions wit
 hin a chemical synapse: hemichannel-mediated ephaptic inhibition in the re
 tina. Current Opinion in Neurobiology 14:1-11.\n\n\nVroman\, R.\, Klaassen
 \, L. J.\, Howlett\, M.\, Cenedese\, V.\, Klooster\, J.\, Sjoerdsma\, T.\,
  & Kamermans\, M. 2014. Extracellular ATP hydrolysis inhibits synaptic tra
 nsmission by increasing pH buffering in the synaptic cleft. PLOS Biology. 
 Vol. 12\, Issue 5. \nAbstract\nNeuronal computations strongly depend on in
 hibitory interactions. One such example occurs at the first retinal synaps
 e\, where horizontal cells inhibit photoreceptors. This interaction genera
 tes the center/surround organization of bipolar cell receptive fields and 
 is crucial for contrast enhancement. Despite its essential role in vision\
 , the underlying synaptic mechanism has puzzled the neuroscience community
  for decades. Two competing hypotheses are currently considered: an ephapt
 ic and a proton-mediated mechanism. Here we show that horizontal cells fee
 d back to photoreceptors via an unexpected synthesis of the two. The first
  one is a very fast ephaptic mechanism that has no synaptic delay\, making
  it one of the fastest inhibitory synapses known. The second one is a rela
 tively slow (t<200 ms)\, highly intriguing mechanism. It depends on ATP re
 lease via Pannexin 1 channels located on horizontal cell dendrites invagin
 ating the cone synaptic\nterminal. The ecto-ATPase NTPDase1 hydrolyses ext
 racellular ATP to AMP\, phosphate groups\, and protons. The phosphate grou
 ps and protons form a pH buffer with a pKa of 7.2\, which keeps the pH in 
 the synaptic cleft relatively acidic. This inhibits the cone Ca2+ channels
  and consequently reduces the glutamate release by the cones. When horizon
 tal cells hyperpolarize\,the pannexin 1 channels decrease their conductanc
 e\, the ATP release decreases\, and the formation of the pH buffer reduces
 . The resulting alkalization in the synaptic cleft consequently increases 
 cone glutamate release. Surprisingly\, the\nhydrolysis of ATP instead of A
 TP itself mediates the synaptic modulation. Our results not only solve lon
 gstanding issues regarding horizontal cell to photoreceptor feedback\, the
 y also demonstrate a new form of synaptic modulation. Because pannexin 1 c
 hannels and ecto-ATPases are strongly expressed in the nervous system and 
 pannexin 1 function is implicated in synaptic plasticity\, we anticipate t
 hat this novel form of synaptic modulation may be a widespread phenomenon.
 g in the synaptic cleft.  PLOS Biology Vol. 12\, Issue 5.\n\nKlaassen\, L.
  J.\, Sun\, Z.\, Steijaert \,M. N.\, Bolte\, P. Fahrenfort\, I.\, Sjoerdsm
 a\, T.\, Klooster\, J.\, Claassen\, Y.\, Shields\, C. R.\, Ten Eikelder\, 
 H. M. M. Janssen-Bienhold\, U.\, Zoidl\, G.\, McMahon\, D.G. & Kamermans\,
  M. 2011. Synaptic transmission from horizontal cells to cones is impaired
  by loss of connexin hemichannels. PlOS Biology Vol.9\, Issue 7.\nAbstract
 \nIn the vertebrate retina\, horizontal cells generate the inhibitory surr
 ound of bipolar cells\, an essential step in contrast enhancement. For the
  last decades\, the mechanism involved in this inhibitory synaptic pathway
  has been a major controversy in retinal research. One hypothesis suggests
  that connexin hemichannels mediate this negative feedback signal\; anothe
 r suggests that feedback is mediated by protons. Mutant zebrafish were gen
 erated that lack connexin 55.5 hemichannels in horizontal cells. Whole cel
 l voltage clamp recordings were made from isolated horizontal cells and co
 nes in flat mount retinas. Light-induced feedback from horizontal cells to
  cones was reduced in mutants. A reduction of feedback was also found when
  horizontal cells were pharmacologically hyperpolarized but was absent whe
 n they were pharmacologically depolarized. Hemichannel currents in isolate
 d horizontal cells showed a similar behavior. The\nhyperpolarization-induc
 ed hemichannel current was strongly reduced in the mutants while the depol
 arization-induced hemichannel current was not. Intracellular recordings we
 re made from horizontal cells. Consistent with impaired feedback in the mu
 tant\, spectral opponent responses in horizontal cells were diminished in 
 these animals. A behavioral assay revealed a lower contrast-sensitivity\, 
 illustrating the role of the horizontal cell to cone feedback pathway in c
 ontrast enhancement. Model simulations showed that the observed modificati
 ons of feedback can be accounted for by an ephaptic mechanism. A model for
  feedback\, in which the number of connexin hemichannels is reduced to abo
 ut 40%\, fully predicts the specific asymmetric modification of feedback. 
 To our knowledge\, this is the first successful genetic interference in th
 e feedback pathway from horizontal cells to cones. It provides direct evid
 ence for an unconventional role of connexin hemichannels in the inhibitory
  synapse between horizontal cells and cones. This is an important step in 
 resolving a longstanding debate about the unusual form of (ephaptic) synap
 tic transmission between horizontal cells and cones in the vertebrate reti
 na.\n\nKamermans\, M.\, Fahrenfort\, I.\, Schultz\, K.\, Janssen-Bienhold\
 , U.\, Sjoerdsma\, T.\, & Weiler\, R. 2001. Hemichannel-Mediated Inhibitio
 n in the Outer Retina. Science. Vol 292. 1178.\n
LOCATION:Hodgkin-Huxley Room\, Department of Physiology Development and Ne
 uroscience
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