Posts Tagged ‘Chemical synapse’

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You already know this, but when you are stressed out (chronic stress), your brain doesn’t work very wellThat’s right – just when you need it most – your brain has a way of letting you down!

Here are a few things that happen to the very cells (in the hippocampus) that you rely on:

reorganization within mossy fiber terminals
loss of excitatory glutamatergic synapses
reduction in the surface area of postsynaptic densities
marked retraction of thorny excrescences
alterations in the lengths of the terminal dendritic segments of pyramidal cells
reduction of the dorsal anterior CA1 area volume

Thanks brain!  Thanks neurons for abandoning me when I need you most!  According to this article, these cellular changes lead to, “impaired hippocampal involvement in episodic, declarative, contextual and spatial memory – likely to debilitate an individual’s ability to process information in new situations and to make decisions about how to deal with new challenges.” UGH!

Are our cells making these changes for a reason?  Might it be better for cells to remodel temporarily rather than suffer permanent, life-long damage?  Perhaps.  Perhaps there are molecular pathways that can lead the reversal of these allostatic stress adaptations?

Check out this recent paper: “A negative regulator of MAP kinase causes depressive behavior” [doi 10.1038/nm.2219]  the authors have identified a gene – MKP-1 – a phosphatase that normally dephosphorylates various MAP kinases involved in cellular growth, that, when inactivated in mice, produces animals that are resistant to chronic unpredictable stress.  Although its known that MKP-1 is needed to limit immune responses associated with multi-organ failure during bacterial infections, the authors suggest:

“pharmacological blockade of MKP-1 would produce a resilient of anti-depressant response to stress”

Hmmm … so Mother Nature is using the same gene to regulate the immune response (turn it off so that it doesn’t damage the rest of the body) and to regulate synaptic growth (turn it off – which is something we DON’T want to do when we’re trying to recover from chronic stress)?  Mother Nature gives us MKP-1 so I can survive an infection, but the same gene prevents us from recovering (finding happiness) from stress?

Of course, we do not need to rely only on pharmacological solutions.  Exercise & social integration are cited by these authors as the top 2 non-medication strategies.

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Walter Dean Myers, an author of The Young Landlords and many other classic coming of age novels once remarked, “The special place of the young adult novel should be in its ability to address the needs of the reader to understand his or her relationships with the world, with each other, and with adults.”  Indeed, the wonderful elaborations of psychosocial development that occur during the teenage years makes for a vivid and tumultuous time – worthy of many a book – especially those like Myers’ that so help adolescents to cope.  During this time, a child’s brain and body is supplanted by adult systems, which, from a physiological point of view, place the adolescent’s mind and body at the mercy of thousands of shifting biochemical processes.  Such a notion of the shifting sands of adolescence were brought to mind while reading a research article focused on one – just one single example – of biochemical change.

The paper entitled, “Cortico-striatal synaptic defects and OCD-like behaviors in SAPAP3 mutant mice” [doi: 10.1038/nature06104] points out that mice who lack the function of the post-synaptic density scaffolding protein encoded by the SAPAP3 gene display excessive grooming and other behaviors reminiscent of obsessive compulsive disorder – a condition that frequently emerges during adolescence.  One of the main findings of the paper is that a normal developmental shift of NR2B –> NR2A subunits of the NMDA receptor does NOT seem to occur – rendering the SAPAP3 mutant mice with an immature form of NMDA receptor.  The authors suggest that this may be the underlying reason for the aberrant behavior, and were able to normalize the mutant mice by re-introducing SAPAP3 protein via a lentiviral-mediated expression vector placed in the striatum.

Gosh.  This NR2B –> NR2A shift is just one example – one grain – in the shifting biochemical sands of development.  Just one of thousands.  How did my brain ever make it through?

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We are all familiar with the notion that genes are NOT destiny and that the development of an individual’s mind and body occur in a manner that is sensitive to the environment (e.g. children who eat lots of healthy food grow bigger and stronger than those who have little or no access to food).  In the case of the brain, one of the ways in which the environment gets factored into development – is via so-called “sensitive periods” where certain parts of the brain transiently rely on sensory experience in order to develop.  Children born with cataracts, for example, will have much better vision if the cataracts are removed in the first few weeks of life rather than later on.  This is because the human visual system has a “sensitive period” early in development where it is extra-sensitive to visual input and, after which, the function and connectivity of various parts of the system is – somewhat permanently – established for the rest of the person’s life.  Hence, if there is little visual input (cataracts) during the sensitive period, then the visual system is somewhat permanently unable to process visual information – even if the cataracts are subsequently removed.  (To learn more about this topic, visit Pawan Sinha’s lab at M.I.T and his Project Prakash intervention study on childhood blindness.)

What the heck is an “in”sensitive period then?   Well, whereas visual input is clearly a “good thing” for the sensitive period of visual development, perhaps some inputs are “bad” and it may be useful to shield or protect the brain from exposure.  Maybe some environmental inputs are “bad” and one would not want the developing brain to be exposed to them and say, “OK, this (bad stuff) is normal“.  As a parent, I am constantly telling my children that the traffic-filled street is a “bad place” and, like all parents, I would not want my children to think that it was OK to wander into the street.  Clearly, I want my child to recognize the car-filled street as a “bad thing”.

In the developing brain, it turns out that there are some “bad things” that one would NOT like (the brain) to get accustomed to.  Long-term exposure to glucocorticoids is one example – well-known to cause a type of neuronal remodelling in the hippocampus, that is associated with poor cognitive performance (visit Bruce McEwen’s lab at Rockefeller University to learn more about this).  Perhaps an “in”sensitive period – where the brain is insensitive to glucocorticoids – is one way to teach the brain that glucocorticoids are “bad” and DO NOT get too familiar with them (such a period does actually occur during early post-natal mammalian development).  Of course, we do need our brains to mount an acute stress response, if and when, we are being threatened, but it is also very important that the brain learn to TURN-OFF the acute stress response when the threat has passed – an extensive literature on the deleterious effects of chronic exposure to stress bears this out.  Hence, the brain needs to learn to recognize the flow of glucocorticoids as something that needs to be shut down.

OK, so our developing brain needs to learn what/who is “good vs. bad”.  Perhaps sensitive and insensitive periods help to reinforce this learning – and also – to cement learning into the system in a sort of permanent way (I’m really not sure if this is the consensus view, but I’ll try and podcast interview some of the experts here asap).  In any case, in the case of the visual system, it is clear that the lack of visual input during the sensitive period has long lasting consequences.  In the case of the stress response, it is also clear that if there is untoward stress early in development, one can be (somewhat) destined to endure a lifetime of emotional difficulty.  Previous posts here, here, here cover research on behavioral/genomic correlates of early life stress.

Genes meet environment in the epigenome during sensitive and insensitive periods?

As stated at the outset – genes are not destiny.  The DNA cannot encode a system that knows who/what is good vs. bad, but rather can only encode a system of molecular parts that can assemble to learn these contingencies on the fly.  During sensitive periods in the visual system, cells in the visual system are more active and fire more profusely during the sensitive period. This extra firing leads to changes in gene expression in ways that (somewhat) permanently set the connectivity, strength and sensitivity of visual synapses.  The expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections are well-known tagets of activity-induced gene expression.  Hence the environment “interacts” with the genome via neuronal firing which induces gene expression which – in turn – feeds back and modulates neuronal firing.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Similarly, in the stress response system, the environment induces changes in the firing of cells in the hypothalamus which leads (through a series of intermediates) to the release of glucocorticoids.  Genes induced during the firing of hypothalamic cells and by the release of glucocorticoid can modify the organism’s subsequent response to stressful events.  Environment –> neuronal firing –> gene expression –> modified neuronal firing.  OK.

Digging deeper into the mechanism by which neuronal firing induces gene expression, we find an interesting twist.   Certainly there is a well-studied mechanism wherein neuronal firing causes Ca++ release which activates gene expression of neuroligins, neurexins, integrins and all manner of extracellular proteins that stabilize synaptic connections – for many decades.  There is another mechanism that can permanently mark certain genes and alter their levels of expression – in a long-lasting manner.  These are so-called epigenetic mechanisms such as DNA methylation and acetylation.  As covered here and here, for instance, Michael Meaney’s lab has shown that DNA CpG methylation of various genes can vary in response to early-life stress and/or maternal care. In some cases, females who were poorly cared for, may, in turn, be rather lousy mothers themselves as a consequence of these epigenetic markings.

A new research article, “Dynamic DNA methylation programs persistent adverse effects of early-life stress” by Chris Murgatroyd and colleagues [doi:10.1038/nn.2436] explores these mechanisms in great detail.  The team explored the expression of the arginine vasopressin (AVP) peptide – a gene which is important for healthy social interaction and social-stress responsivity.  Among many other interesting results, the team reports that early life stress (using a mouse model) leads to lower levels of methylation in the 3rd CpG island which is located downstream in a distal gene-expression-enhancer region.  In short, more early-life stress was correlated with less methylation, more AVP expression which is known to potentiate the release of glucocorticoids (a bad thing).   The team reports that the methyl binding MeCP2 protein, encoded by the gene that underlies Rett syndrome, acts as a repressor of AVP expression – which would normally be a good thing since it would keep AVP levels (and hence glucocorticoid levels) down.  But unfortunately, early-life stress removes the very methyl groups to which MeCP2 binds and also the team reports that parvocelluar neuronal depolarization leads to phosphorylation (on serine residue #438) of MeCP2 – a form of MeCP2 that is less accessible to its targets.  So, in  a manner similar to other examples, early life stress can have long-lasting effects on gene expression via an epigenetic mechanism – and disables an otherwise protective mechanism that would shield the organism from the effects of stress.  Much like in the case of Rett syndrome (as covered here) it seems that when MeCP2 is bound – then it silences gene expression – which would seem to be a good thing when it comes to the case of AVP.

So who puts these epigenetic marks on chromosomes and why?

I’ll try and explore this further in the weeks ahead.  One intriguing idea about why methylation has been co-opted among mammals, has to do with the idea of parent-offspring conflict.  According to David Haig, one of the experts on this topic, males have various incentives to cause their offspring to be large and fast growing, while females have incentive to combat the genomic tricks that males use, and to keep their offspring smaller and more manageable in size.  The literature clearly show that genes that are marked or methylated by fathers (paternally imprinted genes) tend to be growth promoting genes and that maternally imprinted genes tend to be growth inhibitors.  One might imagine that maternally methylated genes might have an impact on maternal care as well.

Lastly, the growth promoting/inhibiting effects of paternal/maternal genes and gene markings is now starting to be discussed somewhat in the context of autism/schizophrenia which have have been associated with synaptic under-/over-growth, respectively.

Building a brain is already tough enough – but to have to do it amidst an eons-old battle between maternal and paternal genomes.  Sheesh!  More on this to come.

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astrocyteIf you compare the left panel to the right panel, you’ll see a dendrite (grey) with dendritic spines (green) on the left-side and then, on the right-side, these spines enveloped by the membrane of an astrocyte (white).  These images were obtained from synapse-web.org who use a method known as 3D reconstruction of serial section electron microscopy – or something like that – to better understand what types of structural factors underlie normal and abnormal synaptic function.  What is so amazing to me are the delicate ruffles of the astrocyte membrane that seem to want to ensheath each spine.  Was any organelle so gently and well cared for?  Perhaps not.  These are dendritic spines afterall – the very structures that form synaptic contacts and process the neural signals – that allow us to think and function.

It turns out that astrocytes not only seem to care for dendritic spines, but also provide the essential signal that initiates the sprouting of neuronal spines in the first place.  As covered in their recent paper, “Gabapentin Receptor α2δ-1 Is a Neuronal Thrombospondin Receptor Responsible for Excitatory CNS Synaptogenesis” [doi:10.1016/j.cell.2009.09.025] Eroglu and colleagues report the discovery – in mice – of CACNA2D1 the alpha-2/delta-1 subunit of the voltage-dependent calcium channel complex encodes a protein that binds to thrombospondins (humans have THBS1 and THBS2) which are adhesive glycoproteins that mediate cell-to-cell and cell-to-matrix interactions – and are required for the formation of new dendritic spines.  When neurons are cultured in the absence of thrombospondins, they fail to produce new spines and mice that do not make thrombospondins do not make very many excitatory synaptic spines.

The interesting twist to me is that thrombospondins are secreted solely by astrocytes! The newly identified CACNA2D1 receptor – as revealed by Eroglu et al., – binds to the EGF-repeats of thrombospondin and initiates a signalling cascade that results in the sprouting of new – silent – dendritic spines.  Gabapentin, a drug that is prescribed for seizures, pain, methamphetamine addiction and many other mental health conditions appears to bind to CACNA2D1 and interfere with the binding of thrombospondin and also inhibits the formation of new spines in vitro as well during the development of somatotopic maps in the mouse whisker barrel cortex.

This seems to be an important discovery in the understanding of how cognitive development unfolds since much of the expression of thrombospondin and its effects on synaptogenesis occur in the early postnatal stages of development.  I will follow this thread in the months to come.

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SfNneuroblogbadge Phrenological thinking, a popular pseudoscientific practice in the 1800’s suggested that the structure of the head and underlying brain held the clues to understanding human behavior.  Today, amidst the ongoing convergence of developmental science, molecular & biochemical science and systems-dynamical science (to name just a few), there is – of course – no single or agreed-upon level of analysis that can provide all the answers.  Circuit dynamics are wonderfully correlated with behavior, but they can be regulated by synaptic weights.  Also,  while developmental studies reveal the far reaching beauty of neuronal circuitry, such elegant wiring is of little benefit without healthy and properly regulated synaptic connections.  Genes too, can be associated with circuit dynamics and behavior, but what do these genes do?  Perchance encode proteins that help to form and regulate synapses? Synapses, synapses, synapses.  Perhaps there is a level of analysis – or a nexus – where all levels of analysis intersect?  What do we know about synapses and how these essential aspects of brain function are formed and regulated?

With this in mind I’ve been exploring the nanosymposium, “Molecular Dynamics and Regulation at Synapses” to learn more about the latest findings in this important crossroads of neurobiology.  If you’re like me, you sort of take synapses for granted and think of them as being very tiny and sort of generic.  Delve a while into the material presented at this symposium and you may come to view the lowly synapse – a single synapse – as a much larger, more complex, ever changing biochemical world unto itself.  The number of molecular players under scrutiny by the groups presenting in this one session is staggering.  GTPase activating proteins, kinases, molecular motors, receptors, proteases, cell adhesive proteins, ion channels and many others must interact according to standard biochemical and thermodynamic laws.  At this molecular-soup level, it seems rather miraculous that the core process of vessicle-to-cell membrane fusion can happen at all – let alone in the precise way needed to maintain the proper oscillatory timing needed for Hebbian plasticity and higher-level circuit properties associated with attention and memory.

For sure, this is one reason why the brain and behavior are hard to understand.  Synapses are very complex!

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