Chinese food, umami, autism, schizophrenia, and cancer

There's a fascinating interrelationship among the things mentioned in the title – and it takes us through equally fascinating topics in molecular cell biology and neurobiology.

No, Chinese food has not been found to cause the listed maladies – although with the additives that the People's Republic of China seems to be allowing in many of its food products these days (e. g. melamine), who knows for sure?

So what's the connection? Try monosodium glutamate (MSG). That, of course, is the sodium salt of glutamic acid (which itself is often referred to as "glutamate"). MSG is a rather well known food additive which at one time was very commonly used in Chinese food for its ability to "enhance" flavor. Technically, the form of glutamate responsible for flavor is the ionic form rather than the sodium salt – the former being what is found in aqueous solution rather than the latter dry crystalline form.

MSG became notorious some time ago when Chinese food became popular in western countries, because it was at first unfamiliar and also tended to cause headaches or at least a peculiar lightheaded sensation after eating food to which it had been added. Consequently, most Chinese restaurants, at least in the U. S., now carefully inform customers that their food "contains no MSG".

Nevertheless, it's impossible to escape glutamate, because glutamic acid is one of the 20 amino acids that make up all proteins. It's essential to life as we know it, and so in fact it can't be avoided.

It also happens to be one of the most important neurotransmitters, and in that role is absolutely essential to the function of animal nervous systems. This role of glutamate is the key part of the story here.

As a flavor, glutamate is responsible for the much hyped "fifth taste" known in Japanese as umami. The first four basic tastes are sweetness, bitterness, sourness, and saltiness. Each of these is detected by specialized receptors on human tongues. Like the others, umami is also detected by its own receptor, but what's actually being detected is the amino acid glutamate present in all protein-containing foods, especially meats, cheese, and soy products.

Although the flavor is enjoyable, it's as a neurotransmitter that glutamate is important for the present story. As a neurotransmitter, glutamate is excitatory. In fact, it's the most abundant excitatory neurotransmmitter in mammalian nervous system. An electrical impulse traveling down a neuron's axon triggers the release of glutamate at the presynaptic side of glutamate synapses. When this glutamate is picked up by receptors at the other side (the postsynaptic side) of the synapse it contributes to possible excitation of the postsynaptic neuron. This is the basic mechanism by which signals are transmitted through an animal's nerves. (But there are other neurotransmitters besides glutamate that may be involved.)

However, this excitatory behavior can get out of hand, and when it does glutamate can have a toxic effect, called excitotoxicity. This can kill neurons and cause disease conditions such as autism, schizophrenia, and epilepsy.

Since glutamate is both essential but also (in excessive amounts) potentially toxic, an elaborate negative feedback system has evolved to keep glutamate production and release under careful control. It is when this feedback system fails somehow that neurological diseases develop. A typical cause of failure is mutation of genes that produce proteins essential to the feedback system.

So what are some of these genes/proteins? The first of these is the metabatropic glutamate receptor, mGluR for short. This is a receptor found on the surface of an axon, close to a glutamate synapse. When glutamate outside the neuron binds to such a receptor, it acts to tamp down the exited state of the neuron that led to release of glutamate in the first place. This process is called autocrine signaling, meaning that it involves a cell releasing a signaling molecule that can trigger a receptor on the same cell to modify cell behavior. This is the start of the negative feedback loop.

One source of failure is in mutation of mGluR itself, if this mutation causes further steps in the feedback loop to fail. What are some of these further steps? The first and possibly most important involves a protein enzyme with the charming name of PI3K. That's short for "Phosphoinositide 3-kinase", and we should be grateful for not having to write it out in full every time.

PI3K is a kinase, which means its enzymatic action is to cause phosphorylation of other proteins. A sequence of phosphorylating kinsaes constitutes a signal cascade or "pathway".

PI3K is the start of a pathway that plays a huge role in cell survival and proliferation – among other things. Clearly, it's an important protein.

The next step in the pathway is another kinsase called AKT. It's actually, in humans, a small family of proteins, Akt1, Akt2, and Akt3. Akt1 is the main player. One of its main jobs is cell survival, as an inhibitor of apoptosis. There are many reasons, both good and bad, for a cell to die by apoptosis. Akt1 is there to prevent the bad reasons for being responsible for too much cell death.

However, in cells that have become cancerous, one or another member of the AKT family typically functions only too well, resulting in the uncontrolled proliferation of cells that is the hallmark of cancer. In fact, an AKT kinase is hyperactive in the majority of human cancers. These molecules have been called perhaps the most frequently activated type of oncoprotein. (Reference: here.) Not only is AKT, in one form or another, involved in a majority of cancers, in many types of cancer, some form of AKT is a key factor. For instance, in melanoma, the interaction of Akt3 and another important cancer-related protein, c-Raf, is involved in 60-70% of melanoma-related tumors. (Reference: here.)

Not too long ago we discussed several other kinases (mTOR and MAP kinases), as well as PI3K and AKT, that play a role in cancer.

Its significant involvement in cancer is far from the only reason AKT is interesting, though. It is a versatile kinase involved in multiple pathways. In particular, it also participates in the negative feedback loop for glutamate because it deactivates a FoxO transcription factor. (For many details on that topic, see here.)

Now we're really getting into the heart of the story on the negative glutamate feedback loop. Recent research on fruit fly motor neurons, which we're about to refer to, suggests (among other things) that an AKT kinase inhibits a FoxO transcription factor that otherwise would stimulate glutamate release.

In a nutshell, the autocrine stimulation of the mGluR glutamate receptor activates PI3K, which activates an AKT kinase, which then inhibits a transcription factor, thereby inhibiting further glutamate release. This negative feedback loop keeps motor neurons from becoming overactive.

Here's a picture of what's going on:



Any mutation of the signaling kinases involved in this feedback loop would, of course, destabilize the control mechanism, but would likely cause other pathology as well, because of the involvment of PI3K, AKT, and FoxO in many other important cellular processes. However, if it was the mGluR glutamate receptor that was affected by a mutation, the main consequence would be some neurological pathology such as epilepsy.

A further reasonable speculation would be that mutations affecting mGluR in other types of neurons could cause other neurological problems, such as autism or schizophrenia. The present research does not actually deal with this more general case. However, other research has implicated PI3K and mGluRs in epilepsy, neurofibromatosis (a type of non-cancerous tumor), autism, schizophrenia, and other neurological disorders in humans.

Here's the research and its abstract:

A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability

Use-dependent downregulation of neuronal activity (negative feedback) can act as a homeostatic mechanism to maintain neuronal activity at a particular specified value. Disruption of this negative feedback might lead to neurological pathologies, such as epilepsy, but the precise mechanisms by which this feedback can occur remain incompletely understood. At one glutamatergic synapse, the Drosophila neuromuscular junction, a mutation in the group II metabotropic glutamate receptor gene (DmGluRA) increased motor neuron excitability by disrupting an autocrine, glutamate-mediated negative feedback. We show that DmGluRA mutations increase neuronal excitability by preventing PI3 kinase (PI3K) activation and consequently hyperactivating the transcription factor Foxo. Furthermore, glutamate application increases levels of phospho-Akt, a product of PI3K signaling, within motor nerve terminals in a DmGluRA-dependent manner. Finally, we show that PI3K increases both axon diameter and synapse number via the Tor/S6 kinase pathway, but not Foxo. In humans, PI3K and group II mGluRs are implicated in epilepsy, neurofibromatosis, autism, schizophrenia, and other neurological disorders; however, neither the link between group II mGluRs and PI3K, nor the role of PI3K-dependent regulation of Foxo in the control of neuronal excitability, had been previously reported. Our work suggests that some of the deficits in these neurological disorders might result from disruption of glutamate-mediated homeostasis of neuronal excitability.

Further reading:

Possible Clues To Root Of Epilepsy, Autism, Schizophrenia (12/9/08) – press release

Eric Howlett, Curtis Chun-Jen Lin, William Lavery, Michael Stern (2008). A PI3-Kinase–Mediated Negative Feedback Regulates Neuronal Excitability PLoS Genetics, 4 (11) DOI: 10.1371/journal.pgen.1000277

Tags: autism, schizophrenia, epilepsy

mTOR, MAPK, and cancer

Recent studies are making it increasingly apparent that cancer is really many different diseases – hundreds actually – in the sense that there are hundreds of distinct problems at a molecular level that can result in the symptoms of cancer in a large variety of tissue types. It is necessary to regard all these problems as distinct diseases, because different techniques will be necessary to deal effectively with each one.

One of the things we are now understanding is that it is not simply mutations in a few specific genes that account for most different cancers. Instead, each different type of cancer can be attributed to mutations in one or several genes randomly chosen from a larger set that collectively defines some specific signaling "pathway" in a cell. Or perhaps even several interrelated pathways.

See here for one account of some of the latest research on this. I'd like to discuss the papers that cover this research, but first I'd like to discuss some slightly earlier research that provides a simpler look at the issue.

I've already written about one particular pathway of special importance, the one associated with mTOR. That discussion, from last April, is here.

As you recall, mTOR is a serine/threonine kinase. The pathway in which it plays a prominent part regulates the growth, proliferation, motility, and survival of cells. And also angiogenesis. From that list it should be obvious why malfunctions in the pathway can give rise to cancer. The pathway, in turn, integrates input from a number of upstream pathways, such as those involving intercellular signaling molecules like insulin, IGF-1, and mitogens.

The name mTOR is short for mammalian target of rapamycin. Rapamycin, also known as sirolimus, is a bacterial product that was originally of interest for its antifungal properties. It was subsequently found to have immunosuppressive and antiproliferative properties. These properties, in turn, are a consequence of the fact that rapamycin binds to a protein complex called mTOR complex 1 (mTORC1). The antiproliferative properties, of course, are due to the importance of mTOR in regulating cell proliferation and motility.

All this stuff is well known to cancer biologists and not new. In particular, much research has been devoted to finding useful inhibitors of mTOR. Unfortunately, however, the research hasn't been as successful at actually treating cancer as might have been hoped:

A Role For MAPK Inhibitors Combined With MTORC1 Inhibitors (8/21/08)

Nearly a decade ago, while it was being tested as an immunosuppressive agent to prevent organ rejection in transplant patients, the drug rapamycin was also discovered to have anti-tumor properties. Since then, several rapamycin analogs known as mTOR (mammalian target of rapamycin) inhibitors have been tested in clinical trials for the treatment of various types of cancer.

But despite promising early results, mTOR inhibitors have proven less successful than originally expected.

The problem is that the mTOR inhibitors that have been tried as anti-cancer drugs also seem to stimulate another pathway that promotes cell growth and proliferation:

Now research led by scientists at Beth Israel Deaconess Medical Center (BIDMC) identifies a previously unrecognized problem faced by these agents when it comes to attacking cancers. ... [T]he new findings show that at the same time that rapamycin analogs are halting tumor growth by inhibiting the mTOR protein complex 1 (mTORC1), they are activating the MAPK (mitogen-activated protein kinase) pathway -- thereby encouraging cancer cell survival.

The MAPK pathway has also been under intensive investigation in connection with cancer. As the name implies, kinases in this pathway are activated by mitogens – external signals that promote mitosis. These kinases also affect cell survival and apoptosis. So it's reasonable to guess that adding a MAPK inhibitor to an mTOR inihibitor might counteract the MAPK-stimulating effect of the mTOR inhibitors.

Are you with me? Anyhow, what the new research does is show how there's a feedback loop that connects mTOR inhibition with MAPK activation.

Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer

Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. ... We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway.

PI3K is another important signaling kinase about which there is a lot of other interesting current research – which we'll get around to discussing at some point. Ras is a G protein known to be very important in cancer because it activates MAPK pathways.

Are you beginning to get the picture of how complicated cancer can be, due to the interaction of pathways?

Fortunately, the research also shows that MAPK inhibition can offset problems due to mTOR inhibition:

[P]harmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors.

Another research group has already confirmed the same thing, using the same MAPK inhibitor (PD0325901):

Anti-tumor Effects Are Enhanced By Inhibiting Two Pathways Rather Than One (8/21/08)

In the second study, Cory Abate-Shen and colleagues, at Columbia University College of Physicians and Surgeons, New York, and the University of Medicine & Dentistry of New Jersey, Piscataway, show that simultaneous inhibition of the mTOR and MAPK signaling pathways inhibited the in vitro growth of prostate cancer cell lines and the in vivo growth of prostate tumors in a mouse model of prostate cancer.

Here's their research paper:

Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model

The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model.

AKT is yet another family of serine/threonine kinases, often associated with mTOR, that is deeply involved in tumorigenicity. There's a lot of recent research on it that should also be discussed... some other time.

Further reading:

From Metabolism to Oncogenes and Back - Part II – 3/21/08 blog post that discusses many cancer-related signaling pathways, including mTOR, AKT, PI3K, Ras, and their connection with metabolism

Arkaitz Carracedo, Li Ma, Julie Teruya-Feldstein, Federico Rojo, Leonardo Salmena, Andrea Alimonti, Ainara Egia, Atsuo T. Sasaki, George Thomas, Sara C. Kozma, Antonella Papa, Caterina Nardella, Lewis C. Cantley, Jose Baselga, Pier Paolo Pandolfi (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer Journal of Clinical Investigation DOI: 10.1172/JCI34739

Tags: cancer, mTOR

TOR signaling and cancer

Another recent development pertinent to the discussion of TOR signaling and cancer (see here), is the announcement of preclinical findings about a potential anti-cancer drug that may act against ovarian cancer. The drug works by inhibiting the mTOR signaling pathway. (mTOR is the mammalian form of TOR.)

This is not at all the first anti-cancer drug that's come along with a similar mechanism of action. But it's still interesting, because any drug that affects TOR signaling has the potential of also causing unwanted side effects, since TOR signaling is involved in so many cell processes. Presumably some effort has been made to find reasons why the effect of the drug should be limited to cancer cells.

The drug is called NV-128, and has been developed by an Australian biotech company called Novogen. Since the drug hasn't yet entered clinical trials in humans, it could take a decade or so (as usual) to perform enough testing to determine that NV-128 is actually effective, and relatively safe.

Anyhow, here's the news release:

Drug Compound Leads To Death Of Ovarian Cancer Cells Resistant To Chemotherapy (4/17/08)

In a discovery that may be useful for maintaining remission in chemo-resistant ovarian cancer, Yale scientists report that pre-clinical studies have shown the drug compound NV-128 can induce the death of ovarian cancer cells by halting the activation of a protein pathway called mTOR.

Many traditional cancer drugs work by triggering cell death via apoptosis. Unfortunately, apoptosis needs enzymes called caspases to work, as explained here. And cancer cells may develop a circumvention of this mechanism by turning down the production of caspases, which are needed to allow mitochondria to respond to apoptosis signals. NV-128, however, is able to overcome this problem by triggering caspase-independent cell death.

In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies. Inhibition of mTOR could shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells.

Here's the Novogen press release:

Novogen’s NV-128 shown to target the akt-mTOR receptor in chemoresistant cancer cells (4/15/08)

NV-128 is unique in that it does not induce caspase-mediated apoptosis which can be non-functional in chemoresistant cancer cells due to accumulated mutations in tumour suppressor/promoter genes and over-expression of anti-apoptotic proteins. Rather, NV-128 uncouples the akt-mTOR­P70S6K signal transduction cascade which has a key role in driving protein translation and uncontrolled cancer cell proliferation. Further, NV-128 induces mitochondrial depolarization via a novel pathway involving the autophagy protein Beclin-1 and Bcl-2, thereby resulting in endonuclease G translocation to the nucleus and cell death.

The same research group that presented the findings just mentioned has also done work on ovarian cancer itself, and been able to locate cancer stem cells for this type of cancer:

Ovarian Cancer Stem Cells Identified, Characterized (4/17/08)

Researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer's recurrence and its resistance to chemotherapy.

As already mentioned, NV-128 is not the only drug under investigation for attacking cancer by targeting the TOR pathway. In fact, almost a year ago, the first anti-cancer mTOR-inhibitor received FDA approval. It's Toricel (temsirolimus), an intravenous drug from Wyeth Pharmaceuticals, for kidney cancer. Novartis has an oral drug (everolimus) for kidney cancer in Phase III trials. (It's already been approved by the FDA as an immunosuppressant to prevent rejection of organ transplants.) Interestingly, and unsurprisingly, everolimus is a derivative of Rapamycin (sirolimus) – an anti-fungal and immunosuppressive compound – which led to the original discovery of mTOR. Everolimus works similarly to Rapamycin as an mTOR inhibitor.

The American biotech company Ariad Pharmaceuticals has a small molecule anti-cancer mTOR inhibitor called deforolimus in intermediate clinical trials for a variety of solid cancers, such as sarcomas, endometrial, prostate, breast and non-small cell lung cancers. The company describes the drug as "a novel small-molecule inhibitor of the protein mTOR, a “master switch” in cancer cells. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis." Last summer Ariad entered into a major partnership with Merck to develop and test the drug, so this is an indication that the drug has definite promise.

Ariad has a nice video you can download, which explains a bit about how their drug works, and about TOR signaling in general. I highly recommend having a look at it, since it covers upstream signals that activate mTOR (growth factors, amino acids, oxygen, energy), downstream effects (synthesis of proteins for cell growth, cell division, metabolism, and angiogenesis). It notes that certain other signaling proteins (PTEN, Akt, PI3K) cause overactivation of mTOR, and it points out that mTOR stimulates the production of the cyclin D cell division protein.

Tags: cancer, TOR signaling

Memory and BDNF

Following up on part of this note, where I discussed relationships between memory and stress, it turns out that there are some interesting things known, related to this, which involve a "neurotrophic factor" called BDNF.

In fact, there's quite a lot to say. Let's begin with an explanation of some terms, a little about BDNF, and a look at some research from the past several years on the relationship between BDNF and memory. Later we'll take up more on how stress and depression enter the picture.

A neurotrophin is a type of protein that promotes the survival of neurons – which is in general a pretty good thing. (We'll get to examples in a moment.) One type of neurotrophin, known as a "neutotropic factor", is a growth factor that affects neurons in particular.

More generally, a growth factor is a proteins that signals certain types of cells to survive, differentiate, or grow. A growth factor that helps a cell survive does so by inhibiting programmed cell death. Other growth factors promote cell division, which results in growth of the tissue that contains the affected cells. Yet other growth factors may induce cells to differentiate into cells of a more specialized type.

An important example of a general growth factor is IGF-1, also known as "insulin-like growth factor 1", which we'll be looking at more extensively in upcoming posts.

In this post we're going to consider the specific neurotrophic factor known as BDNF, the brain-derived neurotrophic factor.

Research has shown that BDNF plays a role in memory formation and in the connection between stress and depression. For example, in rats the stress hormone corticosterone seems to decrease the expression of BDNF, and if stress is persistent, this eventually leads to the atrophy of the hippocampus. Since the hippocampus plays an important role in long term memory, this is one way in which stress can negatively impact memory.

Atrophy of the hippocampus has also been found in humans suffering from chronic depression. There is evidence that suggests a deficiency of BDNF may be at least in part implicated in such depression. For example, various factors (such as the neurotransmitter glutamate, exercise, calorie restriction, and antidepressant drugs) are known to stimulate expression of BDNF – and often ameliorate depression as well.

There's a lot of science behind all this. Let's just look at a few research announcements from the past several years to get a feel for the interactions of BDNF and memory.

Key Pathway In Synaptic Plasticity Discovered (5/23/07)

The researchers studied a major developmental event in newborn rodents. A rapid increases in synapse strength and visual circuit refinement occurs quickly after the animal's eyes first open. It was already known that the PSD-95 protein rushes to visual system synapses soon after eye opening. PSD-95 is a scaffold protein that anchors several types of receptors. Some of these receptors are for the neurotransmitter glutamate, and there is also the TrkB receptor for BDNF (and other neurotrophins).

A positive feedback loop is initiated, in which the NMDA glutamate receptor activates BDNF. BDNF then triggers a signaling pathway involving the kinases PI3 and Akt. This pathway leads to more PSD-95 production, completing the loop. The net result is to make synapses more responsive to BDNF, followed by production of additional PSD-95. Once this loop is started at just a few of a neuron's synapses, the rush of PSD-95 to other excitory synapses of the neuron is on. In this way a few very active synapses can prime larger regions of a neuron for long-term synaptic strengthening in response to subsequent stimulation in the newborn animal.

Proteins Necessary For Brain Development Found To Be Critical For Long-term Memory (9/5/06)

This research indicates that BDNF, which is crucial for the growth of brain cells during development, is also equally important for the formation of long-term memories. The study was performed on the common marine snail Aplysia. When the snails are electrically shocked, the neurotransmitter serotonin is released and promotes the formation of long-term memories associated with the shocks. But when the researchers blocked interaction between BDNF and its TrkB receptor, long-term memories did not form, even though serotonin was still released at synapses. This indicates that serotonin alone was not sufficient for long-term memory formation. Short-term memory formation was not affected. Further investigation showed that interfering with the BDNF receptors blocked long-term enhancement of the connections between the brain cells in the reflex circuit normally induced by the shock treatment.

Drug Triggers Body's Mechanism To Reverse Aging Effect On Memory Process (7/27/06)

A class of drugs known as "ampakines" (so-called because they target AMPA receptors) has been under study and development since the early 1990s to deal with neurological conditions, such as schizophrenia, problems of attention span and alertness, and memory impairment associated with dementia and Alzheimer's disease. The research reported here was conducted by a team that included Gary Lynch, who has long been associated with investigation of the biological bases of learning and memory. (See here for more about Lynch and long-term memory.)

In this study, rats were treated for four days with an ampakine drug. Of particular interest was the effect of the drug on the hippocampus of the brain, because of its known importance in the formation of long-term memories. In the hippocampus areas of rats treated with the drug, it was found that (compared to controls) there was a significant increase both of levels of BDNF and of long-term potentiation (LTP) of synapses (an indicator of memory formation). Further, even though the drug had a known half-life of only 15 minutes, elevated levels of BDNF and LTP were observed as long as 18 hours after drug administration was stopped.

Tiny RNA Molecules Fine-tune The Brain's Synapses (1/24/06)

Synapses between two neurons are formed between locations at the tip of an axon of one neuron (the "presynaptic" neuron) and a dendrite on the body of another neuron (the "postsynaptic" neuron). In order to form a complete synapse, it is necessary for there to be protrusions called "dendritic spines" on dendrites of the postsynaptic neuron. In the process of synaptic signaling, it is these spines that absorb neurotransmitter molecules released by the axon of the presynaptic neuron. Consequently, any mechanism that affects the density of spines on dendrites will affect the total number of synapses that can form between neurons.

It had previously been established that BDNF activates a protein kinase called Limk1, which in turn promotes the growth of dendritic spines and hence the ability of synapses to form. This research on rats studied the effect of the microRNA miR-134 on growth of dendritic spines of hippocampal neurons. It was found that when neurons were exposed to miR-134, spine volume significantly decreased, and synapses weakened. Conversely, when miR-134 was inhibited, spines increased in size, strengthening synapses. However, increased levels of BDNF negated the effects of miR-134, indicating that miR-134 achieved its effect by suppressing Limk1.

More: Spine control

Tags: BDNF, memory