Rapamycin Reverses Learning and Memory Deficits in Mice
June 23, 2008 by Kristina Chew, PhD
Filed under Genetics, Health, Intelligence, Medicine, Neuroscience, Science, Treatment
A letter abstract in the June 22nd Nature Medicine is entitled Reversal of learning deficits in a Tsc2+/- mouse model of tuberous sclerosis. Tuberous sclerosis is a rare genetic disease that affects the central nervous system and causes benign tumors to grow on the brain, kidneys, heart, eyes, lungs, and skin. Those with TSC can also have seizures, mental retardation, behavior problems, and skin abnormalities as well as developmental delays and autism: In fact, half of those with TSC have autism and epilepsy. Mutations in one of two genes, TSC1 and TSC2, been have identified as causes of TSC. The Nature Medicine abstract also notes that “even individuals with tuberous sclerosis and a normal intelligence quotient (approximately 50%) are commonly affected with specific neuropsychological problems, including long-term and working memory deficits.”
In the study, which was carried out by researchers from UCLA, mice were bred to have TSC; they specifically had deficits in learning and memory. By giving the mice rapamycin, a drug that has been approved by the FDA to fight tissue rejection following organ transplants, their learning and memory deficits were reversed. From a press release containing interviews with the study’s researchers:
Rapamycin is well-known for targeting an enzyme involved in making proteins needed for memory. The UCLA team chose it because the same enzyme is also regulated by TSC proteins.
“This is the first study to demonstrate that the drug rapamycin can repair learning deficits related to a genetic mutation that causes autism in humans. The same mutation in animals produces learning disorders, which we were able to eliminate in adult mice,” explained principal investigator Dr. Alcino Silva, professor of neurobiology and psychiatry at the David Geffen School of Medicine at UCLA. “Our work and other recent studies suggest that some forms of mental retardation can be reversed, even in the adult brain.”
“These findings challenge the theory that abnormal brain development is to blame for mental impairment in tuberous sclerosis,” added first author Dan Ehninger, postgraduate researcher in neurobiology. “Our research shows that the disease’s learning problems are caused by reversible changes in brain function — not by permanent damage to the developing brain.”
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“Memory is as much about discarding trivial details as it is about storing useful information,” said Silva, a member of the UCLA Department of Psychology and UCLA Brain Research Institute. “Our findings suggest that mice with the mutation cannot distinguish between important and unimportant data. We suspect that their brains are filled with meaningless noise that interferes with learning.”
“After only three days of treatment, the TSC mice learned as quickly as the healthy mice,” said Ehninger. “The rapamycin corrected the biochemistry, reversed the learning deficits and restored normal hippocampal function, allowing the mice’s brains to store memories properly.”
Regan commented about the study on an earlier post; the researchers’ association of intelligence with learning and memory is particularly interesting to me, and also Dr. Silva’s definition of memory as being “‘as much about discarding trivial details as it is about storing useful information.’” My son Charlie has a great and powerful memory: He never seems to forget a therapist or teacher, a place we’ve been and the route to it, a toy or food or activity that he’s liked a lot. He tends to get stuck—fixate—on those first, earlier things he’s learned and to have trouble learning new things (getting used to new teachers and therapists, going to new places along new routes, playing with new toys and trying new foods and activities). Often it seems that the first of many things is what “something is” for Charlie and teaching him otherwise evokes cognitive dissonance,” as if he’s pushing against something in his brain to accommodate for something new.
I’ve noted Charlie’s longstanding struggles to learn the alphabet and language (both understanding and speaking it). Regarding the alphabet: We started to teach it to him when he was about 3 1/2; he’d had no trouble learning numbers. It has taken years for Charlie to recognize the letters and sometimes he seems to be focusing on certain details of the letters—certain shapes and the fact that to many letters rhyme with “ee”—and not to know what aspects he should focus on.
The further results of this study will be of interest to us. But if there were a medicine to help “reverse” memory and learning deficits, I think that Charlie’s thinking and being would be in many ways the same. He takes in so much of the world around him and I truly think his emotional intelligence is the same as other children his age: As I wrote, my husband Jim has injured his back very seriously and, consequently, has not be able to be at all as active as he is used to and as he loves to be. Jim can barely walk right now (this is my husband who easily runs a mile and a half to train station and through Manhattan streets instead of taking the subway, with a bag stuffed with books and papers). I’ve been explaining to Charlie that his dad injured his back and that Charlie has to do more for himself—-and Charlie has been getting out of bed on his own when I ask (instead of getting tugged and semi-carried; he’s always had trouble getting up in the mornings); he’s pulled on his clothes and grabbed his backpack and run down the stairs for the bus with minimal asking. What is this thing called intelligence, I sometimes wonder?
Jeff Stimpson
Jill Cornfield
“But if there were a medicine to help ‘reverse’ memory and learning deficits, I think that Charlie’s thinking and being would be in many ways the same. He takes in so much of the world around him and I truly think his emotional intelligence is the same as other children his age”
It’s certainly interesting. I can’t say, with the amount of information that I can see, how much Rapamycin would affect an autistic mindset in general. It could be totally, it could be not at all, and I can’t really tell.
Of course, it’s hard to know, since it is both with rats and more specifically with tuberous sclerosis. It’s interesting, regardless.
Cliff
Being needed is powerful. Charlie’s dad and his mom need is help and he is rising to their need. Literally!
Ben has skin anomalies that may be related to TSC. We can’t afford the genetic workup. When visiting the geneticist, they suggested we keep an eye on predictive markers that would show up in adolescence. He is adopted, so we have no family background on this.
I have often wondered about the ‘newness’ factor, which is possibly (how would I know:) one of the few universals across the spectrum , albeit the degree may differ significantly.
Tell Jim to be very careful with that back. Have just recovered (not completely) from same and it was one awful experience from one end of it to the other. Well, the morphine was nice, so much so that I ditched that as soon as possible.
I should have been hiking in Algonquin National Park this week. Oh well.
@alyric, morphine—-if I may ask, did you have to have surgery? he’s caught in the insurance pre-authorization loop to get an MRI—-the past few years of advocating for Charlie have taught us to be better about this.
@Rose, thanks for noting that—has he had other genetic testing?
Ok, so we find something that might help. Now where are the programs to make sure people keep getting the help they need, without mountains of red tape, prescription re-authorizations, or insurance worries about it for Life?
Another point, thanks to Rose for mentioning!!
When do we the people get access to diagnostic tests and services, that we may not even know we need?
I had to see a psychiatrist (paid for by insurance) to find out … about my Sleep Apnea for heavens sake. As my symptoms of depression, fatigue etc, we not obvious enough to my HMO provider for him to recognize the need for referral to a Sleep Specialist. Sooo, I am one of those folks stuck in the boat, I know I have problems, but getting them properly addressed takes years of complaining. That shouldn’t be the case. I have more things I could write about, but feel this lil rant should do for now.
No surgery - yet and I would like to remain optimistic about that:) Only 10% ever need it. Mine is just a garden variety of sciatica - a nasty case - couldn’t walk at all. Doc said that for prolapsed disc - need lots of exercise. I gather (guessing wildly) that Jim has reached the surgical option (?spinal fusion) because he has very serious damage, which mine is not.
Still, broadcasting lots of empathy here, hugs, therapeutic massage, whatever. If I said acupuncture half the Hub would descend amid a froth and roiling. Strange to say I got offered an amazing range of CAM options as advice. I declined, sometimes gracefully but one woman took me by surprise and may never say another word to me again. Good luck with the red tape. They seem to buy it by the truckload up here.
I was kind of hoping that Emily might help decipher the study and whether she sees any experimental design problems. I think I follow the drift of what they were look at, but I don’t want to misrepresent the study, which definitely falls under the umbrella of basic rather than applied research, and I think was more of an effort to identify specific regulatory pathways in TSC than search for treatment.
A couple points that I think I get, that for me make this interesting–that the particular cognitive areas studied (in mice which had specific learning deficits related to hippocampal dysfunction but wild-type (WT) motor, anxiety, social approach, and exploratory behavior) were independent of neuroanatomical changes from tuber formation and seizure status, and that these were discrete functions tested–spatial memory (decoupled from vision, motivation, and perceptual memory), working memory, and discrimination in context (in this case learned fear responses, which the Tsc2+/- demonstrated indiscriminately compared to WT).
This was distinct from Tsc1+/- mice, who displayed a different phenotype for social behaviors.
To me that speaks of that possibility of discreteness of “intelligences”; to mediate specific learning deficits without necessarily removing “personhood” or personality.
They were also able to mediate the morphologic trajectory of another mouse line, which ordinarily leads to gross neuroanatomical abnormalities and premature lethality.
I realize that this is not the most practical of interests, but these kinds of studies are fascinating to me because mental retardation has been (too often I think) considered one of those “that’s that” kind of situations. Reversing some aspects, even if in mice, is something revolutionary.
(Emily or other biochemists out there, please correct and educate, if I got any details wrong).
In re: Jim’s back (I think you get to a certain age and everyone has a back story)–hope it’s not too serious, gets better soon, or at least gets into therapy soon. But it’s a bummer.
“To me that speaks of that possibility of discreteness of ‘intelligences’; to mediate specific learning deficits without necessarily removing “personhood” or personality.”
If it was possible to keep that aspect of autism while eliminating some a different set of issues, it would be still complicated but far more palatable to think about, for me.
Though, in thoughts of mental retardation, it does strike a nerve that mental retardation with autism is considered necessarily a static value. I suppose that’s because, under that statement, I frankly don’t exist.
Oh, and I hope Jim gets better, for sure. That’s certainly no fun to go through, at all, so I hope it’s over ASAP.
Cliff
Am eager for Emily’s comments too. 2 things from Regan’s comment that I’m equally curious about:
(1) the ” possibility of discreteness of ‘intelligences’; to mediate specific learning deficits without necessarily removing ‘personhood’ or personality.” — not sure if the notion of “splinter skills” (which my son does not exactly have, though his intelligence exceeds what he can show of it through language) applies here?
(2) “mental retardation has been (too often I think) considered one of those ‘that’s that kind of situations”—-I think the story about 59-year-old Mary’s birthday meal suggests that intelligence, learning, and change are all possible, throughout the lifespan.
About Jim’s back: I had a problem with a bad disk (in my cervical spine) a few years ago. I made things worse by not taking care of it as quickly as I should have. I got to the point where I was actually thinking about surgery, and managed to convince my doctor to give me a 3rd (third!) round of steroids. That third round of steroids saved me - I have the occasional twinge now, but nothing serious. So I’d recommend pushing hard on the medication before trying surgery. I hope things work out for him. Thanks for your blog!
Kristina;
One doctor wanted him to have fragile-x, and it was relatively cheap…but it wasn’t appropriate and I knew it from the start. The results justified my cynicism…NOT fragile-x!
Honest to God, they said just wait until he’s a teen-ager, and if it’s TSC it will show up in facial angiofibromas. It’s often mistaken for acne, but it’s different. Many parents are unaware of their own TSC until their child encounters it.
Rose
I wanted to tell you this:
My son and I take rapamycin(outside of a clinical study). We both have tuberous sclerosis. And yes, from personal experience he is becoming “un” autistic. And no,it was not that he was only mildly autistic….He was non verbal and is now gaining words, rapidly. I never in my life anticipated *this*…..
Angie Lane