The University of Geneva, and more specifically the Luscher lab, hosted a conference last week called Synaptic Diseases. Since I never got to go to a small conference when I worked in synaptic neuroscience, I decided to attend. The presenter list was stacked, including Malinow, Malenka, John Isaac, Nicoll, Sabatini, Kauer, Bredt, Tomita, and many more.*
Never invite pharma guys to speak
Pharmaceutical companies have poached many neuroscientists: Marc Tessier-Lavigne, Mike Ehlers, and attending this conference, Michael Hutton, David Bredt, John Isaac, and Bai Lu. And I should preface the next sentence by saying all of these men are ten times the scientist I am.
These guys gave terrible talks.
I understand life is different "in industry." Your data is now proprietary, not public domain. You need to shield the specifics of your work from competitors. And as the head of a pharma division, you may not know the nitty-gritty details of all the experiments. But, with the exception of Michael Hutton, the rest of their talks included zero data (and Hutton's was more of a review than a talk). One guy (specific names withheld) talked about potential drugs for glutamate receptors, which consisted of showing chemical structures of existing drugs, and 3D reconstructions of receptors. Another guy talked about how BDNF might be used as a therapy, and how they want to investigate it from the genetic (microarrays!) to the brain level (EEG!). One of them even looked ashamed, averting his gaze to the ground, and stumbling over words.
To me, the whole point of a talk is to present your preliminary, unpublished data. The audience gets the thrill of seeing something new, and the presenter can get feedback. Since (I assume), these pharma guys aren't allowed to present preliminary data, I would recommend never inviting them to give a talk.
With that said, here are the highlights from two talks.
Classically, people think that the difference between inducing LTP and LTD induction is calcium levels: above resting calcium, moderately high calcium induces LTD; while even higher calcium induces LTP. The calcium source for both LTP and LTD (at the hippocampal Schaffer Collateral) is the NMDAR; and indeed you can block LTD with the NDMAR antagonist APV.
For whatever reason, Malinow's lab tried to induce LTP while blocking NMDARs with MK-801. MK-801 is a competitive antagonist that binds to NMDARs differently than APV, and blocks NMDAR currents. And when they tried to induce LTD with MK-801, they could. When they tried to induce LTD with a glycine blocker (glycine is an obligatory co-agonist for NMDAR), they could again induce LTD. Their working hypothesis is that glutamate binding to NMDAR is necessary for LTD, but not ion flow through the receptor.
Since this is a Synaptic DISEASE conference, they had a disease tidbit. Alzheimer's Disease is in part caused by amyloid beta, which comes from amyloid precursor protein (APP). APP can induce LTD when applied in slices, and this LTD can be "rescued" by APV. However, they found that this LTD cannot be rescued by MK-801 or their glycine blocker. In the elevator after the talk, one person claimed that Malinow has been giving versions of this talk for two years.
AMPAR function is enhanced by auxiliary subunits, including TARPs, and cornichons (CNIH). In drosophila, it's know that CNIH is expressed mainly in the Golgi, and probably plays a role in ER exit.
To investigate CNIH function in mice, Nicoll's lab employed an approach similar to their recent Lu paper: they floxed CNIH, and then knocked it (the fuck) out via sparse viral infection of Cre. CNIH-2 KO neurons lost 50% of their surface AMPAR expression, both synaptic and extra-synaptic; CNIH-3 KOs were unaffected; and CNIH-2/3 2KOs lost 80% of surface AMPAR.
To investigate which AMPAR the CNIH were interacting with, they applied CNIH shRNA in GluA1-KO mice, and found that there was no effect of the shRNA. However, in GluA2 KO mice, CNIH did reduce surface AMPAR. Furthermore, Western blot pulldowns showed that CNIH binds to GluA1, but not GluA2. Thus it appears the CNIH selectively bind to GluA1.
To check the CNIH-GluA1 interaction a third way, they expressed GluA1/2, CNIH, and TARPs (y-8) in HEK cells, and measured the desensitization kinetics. GluA1/2 heteromers have longer taus than GluA2/3 (4ms vs 2ms). And here my notes fail me, but the gist of it is that for GluA1, both TARPs and CNIH can bind without interfering with each other. However, for GluA2, TARP binding is dominant, and prevents CNIH binding. Finally, they did a glycosylation assay that shows CNIH-KO mice have immature AMPAR.
Their working hypothesis is that CNIH is involved in ER exit, as it is in the fly, and that CNIH binds to the GluA1 of GluA1/2 heteromers. During the question time, both Malenka and Tomita asked pointed questions about possible compensation: for the CNIH-2 shRNA experiments, by the other CNIH; and for the TARP experiments, by other TARPs.
There were a lot of other good talks, but a lot of them weren't about canonical AMPAR/NMDAR/LTP/LTD, and I can't do them justice here. With no more conferences on the horizon, it's time to get back to the paper trail, both mine and others.
* Comparing this conference to ISOT, it feels like the synaptic physiology field is a lot less gender equal than olfaction. In Geneva, there were 6-7 women out of ~35 presenters. In comparison, at ISOT, there were major talks by Buck, Vosshall, Kristin Baldwin, Kristin Scott, and Bargmann, and those are just the people I can name off the top of my head. Not great, but better. Of course, that's nothing compared to the underrepresentation of black people (2/600 at ISOT and 1 at Synaptic Diseases).