An answer to Prof Tepper about his short comment on our recently published paper

We recently published a paper called “GABAergic inhibition in dual-transmission cholinergic and GABAergic striatal interneurons is abolished in Parkinson disease“.

Prof Tepper briefly commented it on Twitter. Here’s our answer:


Our paper is not some sort of “artefact”. Things are never so simple, they usually have an explanation. The devil, as we all know, is in the details. There are a series of good reasons for missing the dual ACh-GABA synaptic transmission from a subpopulation of cholinergic interneurons (CGINs) in the striatum.

  1. We worked on CGIN-CGIN connections, not on CGIN-SPN (Spiny Projecting Neurons) as Tepper and colleagues did. It is possible that these dual synapses are present in CGIN CGIN connections and not in CGIN-SPN connections. The GABAergic component could be input-specific.
  2. Probability of ACh-GABAergic CGIN-CGIN connection is extremely low in control conditions (about 1 pair from 60 pairs tested), and thus could be overlooked easily. It is indeed like looking for a needle in a hay stack. Not seeing it does not mean that it does not exist. The interesting issue is why they are increased in Parkinson disease and this is a major contribution to our understanding of PD and its pathogenic mechanisms;
  3. To record the GABAergic component, the stimulation protocol of CGIN was quite different from traditional ones: we stimulated presynaptic CGIN only 1 time per 4 minutes, otherwise the GABAergic response was very quickly strongly depressed. The use of light stimulation of channel rhodopsin simplifies life but is not always reliable especially with frequent pulses or trains, unless adequate controls have been made.
  4. Dual GABA /Ach release is not really a scoop including in neighboring areas and this should be acknowledged (Sabatini, Nyiri and colleagues more recently). We shall have to adapt to the notion that dual transmission gives novel perspectives of operation in health and disease. GABA with its dual polarity facilities might play a central role in the pathogeny of PD like in many other disorders (Ben-Ari TINS 2017).

We invite our colleagues to repeat any experiments dedicated to the issue of dual ACh/GABA transmission in controls and PD models.

Y Ben-Ari, C Hammond and N Lozovaya

Nicolas X. Tritsch, Adam J. Granger & Bernardo L. Sabatini Mechanisms and functions of GABA co-release.

Daniel T. Case, Shawn D. Burton, Jeremy Y. Gedeon, Sean-Paul G. Williams, Nathaniel N. Urban & Rebecca P. Seal Layer- and cell type-selective co-transmission by a basal forebrain cholinergic projection to the olfactory bulb.

Arpiar Saunders, Adam J Granger, Bernardo L Sabatini Corelease of acetylcholine and GABA from cholinergic forebrain neurons.

Virág  T.  Takács ,  Csaba  Cserép ,  Dániel  Schlingloff ,  Balázs  Pósfai,  András  Szőnyi, Katalin E. Sos , Zsuzsanna Környei, Ádám Dénes, Attila I. Gulyás, Tamás F. Freund, Gábor Nyiri Synaptic co-transmission of acetylcholine and GABA regulates hippocampal states.

Ben-Ari Y : NKCC1 Chloride Importer Antagonists Attenuate Many Neurological and Psychiatric Disorders. Trends Neurosci. 2017 Sep;40(9):536-554

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