Posts Tagged ‘synaptogenesis’

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The A-to-T SNP rs7794745 in the CNTNAP2 gene was found to be associated with increased risk of autism (see Arking et al., 2008).  Specifically, the TT genotype, found in about 15% of individuals, increases these folks’ risk by about 1.2-1.7-fold.  Sure enough, when I checked my 23andMe profile, I found that I’m one of these TT risk-bearing individuals.  Interesting, although not alarming since me and my kids are beyond the age where one typically worries about autism.  Still, one can wonder if such a risk factor might have exerted some influence on the development of my brain?

The recent paper by Tan et al., “Normal variation in fronto-occipital circuitry and cerebellar structure with an autism-associated polymorphism of CNTNAP2” [doi:10.1016/j.neuroimage.2010.02.018 ] suggests there may be subtle, but still profound influences of the TT genotype on brain development in healthy individuals.  According to the authors, “homozygotes for the risk allele showed significant reductions in grey and white matter volume and fractional anisotropy in several regions that have already been implicated in ASD, including the cerebellum, fusiform gyrus, occipital and frontal cortices. Male homozygotes for the risk alleles showed greater reductions in grey matter in the right frontal pole and in FA in the right rostral fronto-occipital fasciculus compared to their female counterparts who showed greater reductions in FA of the anterior thalamic radiation.”

The FA (fractional anisotropy – a measurement of white-matter or myelination) results are consistent with a role of CNTNAP2 in the establishment of synaptic contacts and other cell-cell contacts especially at Nodes of Ranvier – which are critical for proper function of white-matter tracts that support rapid, long-range neural transmission.  Indeed, more severe mutations in CNTNAP2  have been associated with cortical dysplasia and focal epilepsy (Strauss et al., 2006).

Subtle changes perhaps influencing long-range information flow in my brain – wow!

More on CNTNAP2 … its evolutionary history and role in language development.

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Some quick sketches that might help put the fast-growing epigenetics and cognitive development literature into context.  Visit the University of Utah’s Epigenetics training site for more background!

The genome is just the A,G,T,C bases that encode proteins and other mRNA molecules.  The “epi”genome are various modification to the DNA – such as methylation (at C residues) – and acetylation of histone proteins.   These changes help the DNA form various secondary and tertiary structures that can facilitate or block the interaction of DNA with the transcriptional machinery.

When DNA is highly methylated, it generally is less accessible for transcription and hence gene expression is reduced.  When histone proteins (purple blobs that help DNA coil into a compact shape) are acetylated, the DNA is much more accessible and gene expression goes up.

We know that proper epigenetic regulation is critical for cognitive development because mutations in MeCP2 – a protein that binds to methylated C residues – leads to Rett syndrome.  MeCP2 is normally responsible for binding to methylated DNA and recruiting histone de-acetylases (HDACs) to help DNA coil and condense into a closed form that is inaccessible for gene expression (related post here).

When DNA is accessible for gene expression, then it appears that – during brain development – there are relatively more synaptic spines produced (related post here).  Is this a good thing? Rett syndrome would suggest that – NO – too many synaptic spines and too much excitatory activity during brain development may not be optimal.  Neither is too little excitatory (too much inhibitory) activity and too few synaptic spines.  It is likely that you need just the right balance (related post here). Some have argued (here) that autism & schizophrenia are consequences of too many & too few synapses during development.

The sketch above illustrates a theoretical conjecture – not a scenario that has been verified by extensive scientific study. It tries to explain why epigenetic effects can, in practice, be difficult to disentangle from true (changes in the A,G,T,C sequence) genetic effects.  This is because – for one reason – a mother’s experience (extreme stress, malnutrition, chemical toxins) can – based on some evidence – exert an effect on the methylation of her child’s genome.  Keep in mind, that methylation is normal and widespread throughout the genome during development.  However, in this scenario, if the daughter’s behavior or physiology were to be influenced by such methylation, then she could, in theory, when reaching reproductive age, expose her developing child to an environment that leads to altered methylation (shown here of the grandaughter’s genome).  Thus, an epigenetic change would look much like there is a genetic variant being passed from one generation to the next, but such a genetic variant need not exist (related post here, here) – as its an epigenetic phenomenon.  Genes such as BDNF have been the focus of many genetic/epigenetic studies (here, here) – however, much, much more work remains to determine and understand just how much stress/malnutrition/toxin exposure is enough to cause such multi-generational effects.  Disentangling the interaction of genetics with the environment (and its influence on the epigenome) is a complex task, and it is very difficult to prove the conjecture/model above, so be sure to read the literature and popular press on these topics carefully.

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The human brain is renown for its complexity.  Indeed, while we often marvel at the mature brain in its splendid form and capability, its even more staggering to consider how to build such a powerful computing machine.  Admittedly, mother nature has been working on this for a long time – perhaps since the first neuronal cells and cell networks appeared on the scene hundreds of millions of years ago.  In that case, shouldn’t things be pretty well figured out by now?  Consider the example of Down syndrome, a developmental disability that affects about 1 in 800 children.  In this disability, a mere 50% increase in a relative handful of genes is enough to alter the development of the human brain.  To me, its somehow surprising that the development of such a complex organ can be so sensitive to minor disruptions – but perhaps that’s the main attribute of the design – to factor-in aspects of the early environment whilst building.  Perhaps?

So what are these genes that, in the case of Down syndrome, can alter the course of brain development?  Well, it is widely known that individuals with Down syndrome have an extra copy of chromosome 21.  However, the disorder does not necessarily depend on having an extra copy of each and every gene on chromosome 21.   Rare partial trisomies of only 5.4 million base-pairs on 21q22 can produce the same developmental outcomes as the full chromosome trisomy.  Also, it turns out that mice have a large chunk of mouse chromosome 16 that has the very same linear array of genes (synteny) found on human chromosome 21 (see the figure here).  In mice that have an extra copy of about 104 genes, (the Ts65Dn segment above) many of the developmental traits related to brain structure and physiology are observed.  In mice that have an extra copy of about 81 genes, this is also the case (the Ts1Cje segment).

To focus this line of research even further, the recent paper by Belichenko et al., “The “Down Syndrome Critical Region” Is Sufficient in the Mouse Model to Confer Behavioral, Neurophysiological, and Synaptic Phenotypes Characteristic of Down Syndrome” [DOI:10.1523/JNEUROSCI.1547-09.2009]  examine brain structure, physiology and behavior in a line of mice that carry an extra copy of just 33 genes (this is the Ts1Rhr segment seen in the figure above).  Interestingly, these mice display many of the various traits (admittedly mouse versions) that have been associated with Down syndrome – thus greatly narrowing the search from a whole chromosome to a small number of genes.  20 out of 48 Down syndrome-related traits such as enlargement of dendritic spines, reductions of dendritic spines, brain morphology and various behaviors were  observed.  The authors suggest that 2 genes in this Ts1Rhr segment, in particular, look like intriguing candidates.  DYRK1A a gene, that when over-expressed can lead to hippocampal-dependent learning deficits, and KCNJ6, a potassium channel which could readily drive neurons to hyperpolarize if over-expressed.

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Image by Biking Nikon PDX via Flickr

One of the difficult aspects of understanding mental illness, is separating the real causes of the illness from what might be secondary or tertiary consequences of having the illness.  If you think about a car whose engine is not running normally, there may be many observable things going wrong (pinging sound, stalling, smoke, vibration, overheating, loss of power, etc.) – but, what is the real cause of the problem?  What should be done to fix the car? – a faulty sparkplug or timing belt perhaps?  Such is often the problem in medicine, where a fundamental problem can lead to a complex, hard-to-disentangle, etiology of symptoms.  Ideally, you would fix the core problem and then expect the secondary and tertiary consequences to normalize.

This inherent difficulty, particularly in mental illness, is one of the reasons that genetic research is of such interest.  Presumably, the genetic risk factors are deeper and more fundamentally involved in the root causes of the illness – and hence – are preferable targets for treatment.  The recent paper, “Widespread Reductions of Cortical Thickness in Schizophrenia and Spectrum Disorders and Evidence of Heritability” [Arch Gen Psychiatry. 2009;66(5):467-477] seeks to ascertain whether one aspect of schizophrenia – a widespread and well-documented thinning of the neocortex – is due to genetic risk (hence something that is closer to a primary cause) or – rather – if cortical thinning is not due to genetics, and so more of a secondary consequence of things that go wrong earlier in the development of the illness.

To explore this idea, the team of Goldman et al., did something novel.  Rather than examine the differences in cortical thickness between patients and control subjects, the team evaluated the cortical thickness of 59 patients and 72 unaffected siblings as well as 196 unrelated, matched control participants.  If the cortical thickness of the siblings (who share 50% of their genetic variation) was more similar to the patients, then it would suggest that the cortical thinning of the patients was under genetic control and hence – perhaps – a biological trait that is more of a primary cause.  On the other hand, if the cortical thickness of the siblings (who share 0% of their genetic variation) was more similar to that of the healthy control participants, then it would suggest that cortical thinning was – perhaps more of a secondary consequence of some earlier deficit.

The high-resolution structural neuroimaging allowed the team to carefully assess cortical thickness – which is normally between a mere 2 and 4 millimeters – across different areas of the cortex.  The team reports that, for the most part, the cortical thickness measures of the siblings were more similar to the unrelated controls – thus suggesting that cortical thickness may not be a direct component of the genetic risk architecture for schizophrenia.  Still, the paper discusses several candidate mechanisms which could lead to cortical thinning in the illness – some of which might be assessed in the future using other imaging modalities in the context of their patient/sibling/control experimental design.

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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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caliban missing miranda
Image by shehal via Flickr

“A devil, a born devil, on whose nature
Nurture can never stick; on whom my pains,
Humanely taken, all, all lost, quite lost
And as with age his body uglier grows,
So his mind cankers.”

So says the wizard Prospero about the wretched Caliban in Shakespeare’s The Tempest (Act IV, Scene I, lines 188 – 192).  Although Shakespeare was not a neuroscientist (more to his credit!), his poignant phrase, “on whose nature, Nurture can never stick”  strikes the very core of the modern debates on the role of genes and personal genomes, and perhaps reminds us that our human experience is delicately balanced amidst the interaction of genes and environment.

Among the some 20,500 genes in the human genome (yes, this is the latest estimate from Eric Lander this past weekend) one particularly amazing gene stands out.   CACNA2D1 the alpha-2/delta-1 subunit of the voltage-dependent calcium channel complex (which also binds to the widely-prescribed drug Gabapentin) encodes a protein who, in conjunction with other related subunits, forms a calcium channel to mediate the influx of calcium ions into neurons when membrane polarization occurs.  In the recent article, “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 reveal that this single gene – initiates the development of synapses – the dynamic structures whose ever changing interconnections make us who we are – that allow “nurture to stick” as it were.

More on the biology of CACNA2D1 and its interactions with its ligand – Thrombospondins – to come.

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