I’ll start to introduce our next speaker people there still seats available in the front row please do Strickling while I’m doing the introduction so our last session first speaker is our very own dr. mark bear hits the peak our professor of Neuroscience at our pure Institute for learning and memory and the department brilliant cognitive science at MIT he’s a man do not need does not need a whole lot introduction welcome it’s so nice to be back at MIT so well i dapped agree with what Danny said this has been a mind altering experience and really enjoyed the talks today and the breadth of the topic I also have to agree with Matt I standing on the shoulders of giants and I must say that i was forced out of my comfort zone a little bit and trying to come up with a talk that i thought would be of interest to such a broad audience is this considering what we spend our time doing in the laboratory so here it goes so we all know that there are many ways to mess up brain development and these include early childhood adversity disease and heredity and so we can conceptualize this in the following way where we have a some measure a brain maturation of course there’ll be different many different measures of brain maturation depending on what what’s the process that we’re interested in but in general there’s a trajectory of normal brain development and in the face of disease or genetics this development can be derailed in which case there’s an accumulated deficit and so we’ve heard a lot of really inspiring talks today about how one might prevent some of the damage that occurs particularly with early life stress but the issue I want to address in my brief presentation today is what are the prospects for treatment once a diagnosis has been made or a problem has been identified so this is the big question we’re going to we’re going to address and you can imagine really three different scenarios ranging from quite pessimistic to wildly optimistic so the pessimistic scenario is that by the time of diagnosis has been made and a treatment has been begun it’s really too late we’ve missed a critical period that any intervention we can do would be at best palliative and in no way disease modifying the most wildly optimistic scenario is that the treatment actually corrects the core pathophysiology of the disease or maybe even replaces genes that are missing that cause the disease there’s actually a correction of this trajectory of altered brain development so that actually with time and training it can recover normal function and finally this of course an intermediate stage which I call the hopeful scenario which is that it’s never too late to intervene and it will always be some benefit even if that means a reduced rate of decline in function so today I’m going to tell you about two short vignettes about two projects we are going in a lab that are relevant to this theme and what I’m going to convince you is that we can exploit knowledge of neurobiology to repair genetic disorders of brain development and overcome gillett arias effects of impoverished early experience so one of these is a disease called fragile X which is a genetic disease of brain development and a second is a human clinical condition that’s caused by poor quality division during infancy and early childhood so let me begin with fragile X so fragile X is a disease that is caused by the transcriptional silencing of a single gene in the genome so it’s a single gene disorder it’s relatively rare it affects about one in four thousand males and half as many females and it’s a consequence as I said a silencing of this bein called fmr1 and the failure to express a protein called MRP and as a consequence of this one failure of genetics is a syndrome that is multifaceted and very disruptive to the both to the affected individual end of the family so originally this was called fragile X mental retardation years ago because a prominent feature future of just about every one that carries this mutation is intellectual disability but in addition to intellectual disability and cognitive impairment there are a number of different comorbidities that

you could categorize in a number of different ways I think it’s useful to consider some heights we might call hyperreactivity or hyperexcitability phenotypes that can include an increased incidence of early childhood epilepsy everyone with fragile X has autistic features aspects of social phobia gaze avoidance eye contact avoidance repetitive and stereotyped behaviors and children with fragile X can be identified based on a number of dysmorphic features such as a protruding jar or ears that stick out fragile X is often referred to as the leading known heritable cause of autism because just about everyone with fragile X will fall in the autism spectrum and a third will get the full diagnosis of autism so the disease itself was first described back in the 40s by two astute clinicians Martin and Bell who identified a cohort of their patients that had comp features in common most notably intellectual disability but also other physical features and other behavioral features and Martin Bell suspected a genetic etiology and of course it took many decades to identify what that ideology was it required the discovery of the structure of DNA and the sequencing of the human genome but eventually in 1991 a group led by Steve Warren at Emory University identified the gene that’s affected and shortly thereafter a knockout mouse was made that is a mouse that carries the same gene mutation or a gene mutation that causes the failure of expression of this fmr pea protein so this fragile X knockout mouse has been around now for quite a few years and it really attracted the interest of two groups of investigators those who are interested in this disease fragile x syndrome and those who are interested in the protein fmr p turns out FM RP is very interesting it’s highly expressed in the brain and at synapses and in fact both the protein and the messenger RNA existed sent asses and so there has been a lot of interest in the potential role of this protein and synaptic plasticity which is what we’re interested in and so I fall in that latter category frankly when we began I hardly knew what fragile x syndrome was but I was quite interested in the protein well in the course of studying how synaptic function is altered in the absence of this protein we made a small discovery and the small discovery was that a phenomenon we were studying a form of synaptic plasticity that’s triggered by activating a particular type of glutamate receptor the metabotropic glutamate receptor 54 m gu r5 we found that this form of plasticity was exaggerated in the fragile X knockout mouse and on its own is a modest finding and you know we shopped it around eventually published in the Proceedings of National Academy but we were excited by it because we suddenly realized that perhaps many aspects of fragile x syndrome could be accounted for by excessive activation of this particular neurotransmitter receptor so this idea became known as the in glue our theory of fragile x and we and many other groups around the world have tested this idea and by 2007 there was a consensus that engler 5 was a potential therapeutic target and fragile x and shortly thereafter drug trials were initiated in her ongoing right now to test the efficacy of in glue or five inhibitors and other drugs that probably act in the same mechanism in human fragile x so as i said we really began we began with an interest in synaptic plasticity and we are particularly interested in this metabotropic glutamate receptor him you are five because it was becoming apparent that it was part of a molecular machine that ensures that the supply of synaptic teens keeps up with demand and in this case demand is registered by the release of glutamate by active neurons so the more active your brain is the more glutamate is released the more the in blue are five receptor is activated and that this activation of this receptor triggers the translation of messenger RNA that already exists as sentence is translated into proteins that are important to sustain synaptic function and like any molecular any machine there are important control mechanisms and one of these is provided by this F MRP protein so if you imagine you are five is like the accelerator on a car the f MRP proteins like the brakes so it turns out it’s an mrna binding protein and it gums up the works and slows the rate of translation in response to in blue are five so in the absence of F MRP what happens is is that the brakes are missing so even tapping on the accelerator has exaggerated consequences and you can imagine how that would disrupt function or navigating down the southeast Expressway and so as I said that alone with of some interest but it was really when we started putting all

the pieces together realize that many of that very large constellation of symptoms that goes along with fragile X might many of those could be accounted for by excessive activation of this receptor and so we wondered if exaggerated consequences of Mingora 5 activation provided a thread that would connect these widely dirties really diverse symptoms and fragile x and as i said this has became known as the in glory of fragile x and it’s based on a simple assumption that many of the neurological and psychiatric consequences of fragile x are due to exaggerated activation of em gor receptors and with where one very important consequence and the important consequence is that if we could dial back signaling through the Inga or five receptor we might be able to correct many aspects of fragile x syndrome so we set out to test this idea and perhaps the most definitive way to do this was to cross fragile x mice with another line of mice that had half the normal level of the un’goro scepter so what we’re going to try to do is to see if we could improve the course of fragile X in the mice by reducing the in glorify receptor expression fifty percent and maybe bring the accelerator you know take our foot off the accelerator if you will and so cool Dolan did this when she was an MD PhD student in the lab crossing fragile X knockout mice with the in Blu r5 heterozygous mice to create mice of four different genotypes and what Google described was in about eight eight different phenotypes ranging from anatomical disturbances in the microstructure of the cortex to electrophysiology to biochemistry to behavior including some simple learning and memory tasks that merely by reducing and glorify receptor expression by half was enough to correct all these varied phenotypes so this is good validation of angular 5 as a target but of course that doesn’t mean it could be translated into an effective therapy because that manipulation was a germline manipulation so those animals grew up with half the normal levels of anglo five receptors so we anticipated fragile x syndrome and those animals we’re able to really prevent it so it really left unanswered the question in a human setting once the diagnosis is made which can be at two years of age is it still possible to correct this core pathophysiological mechanism to see an improvement and so to examine this question what we required was good drugs particularly a good in glower five inhibitor with a long half-life that we could use for chronic dosing studies and fortunately our colleagues at roche not only came up with such a drug but they were willing to share it with us so we had a collaboration with a group at roche load led by Lothar lindemann and they developed a kamala Kuehl called seat app which is a highly selective in glorify VIN hibbett ER but as an unusual property that has got a very long half-life at 18 hour half life so they are able to show was is that with every other day dosing you could have a more or less constant receptor occupancy as its model here in this graph so we could block about eighty percent of the ingre or five receptors with every other day dosing which is you know something that graduate students are willing to do and so the the design of the experiment was that the animals were reared normally up to P 30 in a mouse at which time many all these symptoms all these phenotypes that we study have emerged and then treatment was begun and as the title boldly declares we were able to reverse many of these phenotypes essentially all the phenotypes we were able to reverse with the genetic rescue strategy and then some so of course I highlight my own work but this has really been a community effort so the idea that M glorify van de Biche you might help fragile X was first presented back in 2002 and the community the fragile X community really rose to the challenge to test this idea and I can tell you it was met with considerable skepticism in the early days for good reasons but in no other field of science that I’ve ever been involved in has there been such such a strong consensus so that the last time I did a thorough review which was as you can see two years ago but already there were 31 different papers published from different groups looking at 40 different mutant phenotypes and most importantly in three different species so not just the mouse model of fragile x but also a zebrafish model of fragile x and a fruit fly model of fragile x and in all these studies they’ve reported that inhibiting either the in blue are five receptor or the signaling pathway downstream of the NGO are five receptor was sufficient to ameliorate mutant phenotypes so I stress

this because you know now there’s a lot of scrutiny about the you know failure to replicate many particularly animal studies and between labs and so on and so forth but you know this is really reassuring so this was many independent investigators many who didn’t have a stake in the in go our theory like I did you know as I said different species many different assays and a lot of approaches not not one molecule not one genetic approach but many dozens of approaches so this is a particular be well validated target so some of the lessons that we have learned just doing this work is this that one advantage we had in fragile x over some of these more complex disorders is that it has a defined genetic etiology so we have an animal model that’s that’s valid it’s wonderful to see the fundamental synaptic biology revealed signaling defects that suggested a therapy so that means you know the century of work that we’ve been doing on basic neurobiology can have a payoff in terms of therapy ins in addition to just knowledge there can be evolutionary conservation of core pathophysiology was an extremely important point in terms of you know increasing your confidence that you might go to translate these insights into humans disease-modifying treatments are feasible and treatment can be successful after symptom onset and I just want to say that I’ve been talking about fragile s because this is what we work on but there are other single gene disorders that are listed here for which others mainly have also found that there it is possible to do disease modification with small molecule therapies and even when those therapies are begun after adolescence so it’s a lot of optimism in the field that we might be able to fix these diseases that used to be thought to be intractable so our work is done and that we can sit back and let well okay so this is where we are so we have extremely well validated target and now all we needed to do is complete the circle well it turns out that’s a lot harder than you might imagine and I probably didn’t appreciate this going into it very well but what is required is a lot of good guesses okay so you know you have to guess would you know what’s the right patient selection what’s the right molecule what’s the right dose what’s the right treatment duration what are the right endpoint measurements and so on so with every one of those decisions you know no matter how smart you are how many experts you convene it’s not a sure thing and it did remind me a little bit of the warren buffett challenge where you know he was quite confident that his billion dollars was secure because nobody was going to be able to guess 32 basketball games and get them all right and of course he was he was correct so you know we can do the back of the envelope literally calculation I’ve shown here I should say this was this envelope was addressed to the Internal Revenue Service and so I guess I missed that payment but in a case oh I I just this is just off the top of my head some of the things that had to be guessed right and I gave myself a pretty high probability that i would guess right no point a probability for each of these things but of course by the time you multiply all those probabilities together the chance of succeeding in any one clinical trial is is low and this is why it is very expensive to get medications approved and obviously need to be either extremely lucky or prepared to fail before you can succeed and so I just want to say that you know I’ve been involved in clinical trials i founded a company to pursue clinical trials and here’s some of the data and this is a phase 3 trial if this trial had succeeded there was a chance the FDA would approve this medication for fragile x um these are some of the measurements that we guessed would be moved by treatment we had three different doses and the treatment duration eight weeks and you know here the here the p-values and all extremely encouraging I think you could say this is this is great you know if you got this in there and your mice you’d be really excited about it you’d want to follow up on it and in fact we achieve statistical significance in one measure called the aberrant behavior checklist irritability subscale but this is a failed trial and it’s a failed trial because this was not declared to the FDA to be the primary endpoint that was declared to the FDA be the primary endpoint and that is not P lesson point 05 so that’s a failed trial so we read the media about failed failed trials failed trails it doesn’t mean the targets no good or the molecule is no good or you don’t have the right

approach but it means that you didn’t get lucky on the guesses that you made so now I want to shift gears to talk a little bit about amblyopia and the time I have remaining and so looking effective overcoming sensory deprivation so amblyopia is a severe loss of vision usually confined to one I that’s caused by a number of developmental mishaps including the misalignment of the eyes or differences in refraction in the two eyes or a loss of foreign vision in one eye that was you know one cause would be a cataract and one eye or another as a droopy eyelid in one eye and as a consequence of this deprivation of normal vision and infancy and early childhood you lose visual acuity and it can be very severe and over 50 years ago Hubel and Wiesel introduced an animal model in which we can study this and so they were of course pioneers and looking at the organization a descending visual pathway and in one important series of experiments they asked what happens if we deprive one I of normal pattern vision either with an overcorrecting contact lens or a patch or by merely gluing the eyelids together and what they discovered was that there’s a stereotype choreography of changes in the cortex so that cortical neurons stop responding to stimulation of the deprived I and usually over time this compensatory increase in the strength of the responses to the non deprived I so one way you can demonstrate this is with electrophysiology so we can put a microelectrode in primary visual cortex and so what what these histograms show our action potentials that are collected in response to showing a visual stimulus to the right eye or to the left eye and in a normally rear these experiments were done in kittens originally in a normally reared kitten you can see that here’s a neuron it responds well to stimulation of both thighs with a slight preference for the right eye but after a period of an ocular deprivation where that lie wood was closed they opened up the eye and look what happened the neuron stopped responding to stimulation of the right eye and this is just a histogram showing a whole large population of neurons so it’s a very robust phenomenon it’s called ocular dominance plasticity so what are we going to do about it so this is a cartoon that Pavan sand hot gave me which i think is so fantastic I’m going to read it to you because if any are blind as I am in the back row you’ll be able to see this but so this is a I can’t remember which character that is is that no that’s not Lucy patty it’s peppermint patty ok so peppermint patty said I suppose you’re wondering why I’m wearing this eyepatch eight Linus you prep Linus replies you probably have amblyopia x + + op sia the vision of your right eye is so dim so the doctor is patched the left left one thus forcing the right I to work actually treatment of amblyopia is one of the most rewarding and medicine without medication or surgery or hospitalization a child can be given eyesight in an eye which otherwise might have no site and you can see her response so Linus is a very smart guy but the ophthalmologists were pretty smart too because they realized that it’s possible to restore vision in an eye that has been weakened by deprivation by closing the good eye and forcing the week I to to work ok and so this can be done strated electrophysiological e as well so here’s a neuron again this is now after a period of an ocular deprivation so this Duran only responds to to the open I here doesn’t respond to this side now what’s happened is has been a reverse occlusion so the seeing eye is closed the open eyes closed the week I is opened and I just want you to think about what happens to that moment okay at that moment you have a brain that is receiving input through an eye that has been disconnected and it’s receiving no input through an eye that is strong so essentially from the point of view of the brain there’s activity would go would fall precipitously but nonetheless over time there is a recovery of activation by this previously deprived newly-opened I and unfortunately it usually comes at a cost that the previously strong I lose a strength so a lot of this patching requires a little finesse to get it right so you don’t mess up the other eye as well but the question is is what can we learn about how to make weeks and apps as strong and promote recovery of function by studying this and that same phenomenon occurs in mouse visual cortex and virtually everyone in the field works in mice

these days and so in a mouse the it just so happens that the mouse comes the visual cortex comes dominated by the eye on the opposite side the contralateral I so these are the evoked responses from the contralateral I and the ipsilateral I but what happens if we patch the contralateral I well what happens is the contralateral I responses go down but the thing that’s a particular interest here is is that the non deprived I responses pop up and it usually takes about seven days okay so there’s a delay but these responses pop up and one interesting feature in the mouse is that the same thing occurs in the adult mouse as well okay so what’s going on well here’s a couple of features of this open I potentiation so this is what happens normally so I’ve plotted here the duration of deprivation of the other eye and is the response to the non deprived I and you can see that nothing happens for about three or four days and then it slowly comes up so by seven days it’s about double and strength now this is not merely a homeostatic adaptation because it doesn’t occur if you put the animals in the dark so it’s not the absence of visual experience it requires visual experience to see this change and it’s completely blocked by an nmda receptor antagonist okay aha so that’s a you know a drug that we know block synaptic plasticity so we know a lot about NMDA receptor dependent plasticity and what we know is that nmda receptor activation triggers both synaptic strengthening and synaptic weakening and what you get out of an MDA receptor depends on how strong is activated so if it’s strongly activated you get synaptic potentiation long-term potentiation and if its weekly activated you get long-term depression and as a balance point here or what we might call a modification threshold where Ltd depression is converted to potentiation and we further know that this crossover point is itself modifiable so this can adjust depending on a number of factors okay so that’s what we know about NMDA receptor dependent plasticity so perhaps what happens when you do with this reverse patching experiment is that you slide the modification threshold to the left to now make possible synaptic potentiation that previously couldn’t occur so we can test that idea it’s quite easy actually you can take mice or rats or your cat through put them in the dark for a couple of days and ask does that shift the properties of nmda receptor dependent synaptic plasticity and the answer is yes it does and we described as many years ago so you put the animals in the dark for a few days and this LT p ltd curve if you will shifts to the left and it promotes LTP so that makes this week otherwise weeks and apps gives it a toehold to start to undergo synaptic potentiation now there are probably a dozen different mechanisms that contribute to this effect but one of the ones that we’re confident on we know is a change actually in the molecular subunit composite of the NMDA receptors themselves so when you put animals in the dark the subunit composition of the receptors changes so there’s a reduction in what’s called the NR 2 A to B ratio subunit ratio and when the animals are restored to the light that ratio goes back up and we know that changing that ratio will promote or inhibit long-term potentiation so is this related to this recovery of function well it seems to be because we can now do these simple monocular deprivation experiments in mice where we reduce the expression of nr2a the NR to a subunit by other half are completely and that’s what’s summarized here is a study that we did some years ago showing now just with three days of deprivation which normally would produce a very modest you know non significant increase in that in the response to the non deprived I in the nr2a heterozygotes we see that that achieves statistical significance and it’s really gangbusters in the NR to a complete knockout so manipulating the NR to heb ratio is one way that you can promote recovery of function or make weeks and apps is stronger and in fact their companies actually now looking at in our to a specific receptor antagonists to try to do just that to promote synaptic potentiation okay so this is what we thinks going on is that initially we we close the strong I and we set up a situation in the cortex where it goes quiet because it’s seeing through an eye that’s too weak to drive a response and the eye that’s strong enough to drive a response isn’t seeing so the cortex is quiet as a consequence there’s an adjustment a property called meta plasticity the change including a change

in the NR 2 A to B ratio and eventually over time this is sufficient for experience through this week I to start to drive those synapses up and you start to restore our response so what about treating amblyopia and maybe by extension other disorders that are caused by early environmental deprivation well it’s not at first blush it’s it’s not quite so optimistic and in fact even we’ve known this since the 70s since the late 60s again beginning with the work of you won’t weasel who showed that the consequences of deprivation diminish with increasing age and then subsequently Blake more advanced sliders and many others had looked at the effect of reverse patching and this is just happens to be data from Blake more advanced sliders done in kittens but it makes the point that their ability to reverse the effects of deprivation falls precipitously in the cat so that by 12 to 14 weeks of age it’s really immutable okay there’s no recovery as possible and this is a feature not just of kittens but also monkeys and in humans and this is why when you do reverse patching experiments in humans you’ve got to do it before the age of seven otherwise it’s too late so here’s an example of in a cat just showing this meager recovery that would that occurs and this is an interesting experiment done by Don Mitchell at Dalhousie we’re just with a brief period of monocular deprivation and a young kitten and then what he did was open up the eye and he looked at the visual acuity of the deprived I and the non deprived I and this is measured behaviorally not just electrophysiological and so what you see is is that here’s the visual acuity through the deprived I you can see it’s zero so the animal is blind and it does drift up but it doesn’t drift up it is sort of parallels the acquisition of acuity through the non deprived I’m okay so there’s no is sort of what i called the hopeful scenario by restoring vision it does improve with age but it’ll never catch up all right so this is consistent with human clinical experience as well but you know I showed you already if you were paying attention that in the adult mouse we’re still able to get this really dramatic plasticity and at first this took us by surprise well I guess it still takes us by surprise but the NAS visual cortex is is really extraordinarily modifiable even in adults and so it begs the question are my so different I just happen to like this picture so I had to figure out a way to get it in here but and and the question is really they could be different evolution but it could be that we just haven’t really exploited the mechanisms that are available in there in the appropriate way and so what Don did was he try he he did an experiment to exploit this property of meta plasticity ok and so what he did was he took these animal this animal this is one kitten up at the age of 60 days ok no further recovery as possible and they put them in the dark for 10 days and brought them out of the dark ok put him in the dark quiet of the cortex change the NMDA receptor subunit composition etc bring them into the light and now look what happens to the deprived our response over the course of just a couple of days it soars and it achieves absolutely normal monocular cue ities a complete reversal the effect of amblyopia so this is really exciting finding so I’m pretty sure my time is up I hope it is because that’s all I have to say but just just some of the lessons that we’ve learned from our studies of visual cortex is well first there is a lot of plasticity an adult cerebral cortex far more than is historically appreciated so this is great news for all of us all of us um that uh that we just have to figure out how to gain access to these mechanisms but they are they are present they are there and they can be exploited if we’re clever about it the knowledge of synaptic plasticity and meta plasticity suggest approaches to promote recovery of function and as I’ve shown you we can rejuvenate weeks and apses by excluding exploiting this property of meta plasticity but I don’t have didn’t have time to talk about work that’s going on in other laboratories other approaches but all of which are based on knowledge of house and apps is modify and trying to use that knowledge to promote recovery and with that I just want to say thank you to well of course all the people in my lab that that did the work and I want to thank the funding agencies that have support us particular

I want to point out the pic our Institute Innovation Fund and the pic our neurological disease research fund these are creative funding mechanisms that we enjoy here in the pic our Institute thanks to Barbara and they really helped us to push the envelope in ways that wouldn’t be possible with traditional sources of funding so thanks

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