Category Archives: plasticity

synaptic plasticity: angelman’s/autism and psychosis

There is a recent article in Nature Neuroscience by Philpot et al regarding how experience-dependent synaptic plasticity is downregulated in Angelmans’ syndrome and perhaps in Autism too, as the Ube3a gene involved is implicated in both disorders.

First a little history about Angelman– it is a disorder caused by deletion/lack of a maternally imprinted UBE3a gene in chromosomal region 15q11-q13 . It is typically contrasted with Prader-Willi syndrome which is caused by a paternally imprinted gene malfunction in the same chromosomal region. Christopher Badcock has used this to contrast Autism (related to Angelman) and Psychosis (more common in PWS) to argue that Autism and Psychosis are due to a genomic imprinting tug of war between fathers and mothers genes.

I have written about Badcock’s and Crespi’s thesis before and how it fits in with my views on Autism and Psychosis; suffice it to say that I am seeing the new study primarily from this prism of Autism and Psychosis dichotomy.

First , let us see what the study tells us:

It uses mouse model that contains silenced maternal Ube3a genes (Ube3a m-p+ mouse), thus trying to make a mouse model of Angelman.

What it found was:

1)    Ube3a expression was markedly reduced in Ube3am-/p+ mice compared with wild-type mice in all three brain regions (visual neocortex, hippocampus,cerebellam). Consistent with previous observations, this attenuation was brain specific, as Ube3a was highly expressed in the liver of both Ube3am+/p- and Ube3am-/p+ mice.

2) To determine the physiological consequences of Ube3a loss on neocortical development, we examined the developmental acquisition of spontaneous excitatory synaptic transmission by recording miniature excitatory postsynaptic currents (mEPSCs) in layer 2/3 pyramidal neurons of visual cortex (see Supplementary Table 1 online for intrinsic membrane properties of recorded neurons). Consistent with previous findings24, 25, mEPSC amplitudes decreased and frequency increased during development in wild-type mice . Just before eye opening (postnatal day 10, P10), mEPSC frequency and amplitude were indistinguishable between wild-type and Ube3am-/p+ mice . Thereafter, mEPSC frequency failed to develop normally in Ube3am-/p+ mice

3)Although dark rearing had no measurable effect on mEPSC amplitude in wild-type mice at P25 , sensory deprivation strongly attenuated the normal developmental increase in mEPSC frequency in wild-type mice . In contrast, dark rearing did not affect mEPSC amplitude or frequency in Ube3am-/p+ mice. Consequently, mEPSC frequency in normally reared Ube3am-/p+ mice was not significantly different from that of dark-reared wild-type mice . These findings demonstrate that, although Ube3a is not necessary for the initial sensory-independent establishment of synaptic connectivity, it is selectively required for experience-dependent maturation of excitatory circuits.

4)We therefore compared the properties of neocortical long-term depression (LTD) and LTP at layer 2/3 synapses in visual cortex of wild-type and Ube3am-/p+ mice at both young (P25) and adult (P100) ages. Because layer 2/3 pyramidal neurons receive major inputs from layer 4 pyramidal neurons, layer 2/3 field potentials were evoked by layer 4 stimulation . We began by measuring LTD in young mice using a standard stimulation protocol (1 Hz for 15 min). Although LTD was reliably induced in young wild-type mice, it was absent in young Ube3am-/p+ mice . We also observed deficits in LTP induction. A relatively weak induction protocol (three 1-s trains of 40-Hz stimulation) elicited LTP in young wild-type mice, but failed to reliably induce LTP in young Ube3am-/p+ mice . To test whether the neocortex of Ube3am-/p+ mice was capable of expressing LTP, we also applied a strong LTP stimulation protocol (two 1-s trains of 100-Hz stimulation). This protocol consistently induced LTP in both Ube3am-/p+ and wild-type mice. Thus, as with LTP deficits in hippocampus8, 9, the LTP induction machinery is impaired in the visual cortex of Ube3am-/p+ mice and this deficit in LTP can be overcome with strong stimulation.

5)To determine whether the plasticity deficits in Angelman syndrome mice persisted into adulthood, we tested LTD and LTP in adults (P100). In adult wild-type mice, LTD induced by 1-Hz stimulation was absent, as expected27, whereas LTP could be induced with strong stimulation. In adult Ube3am-/p+ mice, however, neither of these protocols were effective at modifying synaptic strength. These results indicate that wild-type mice show attenuated neocortical plasticity as they mature and that this attenuation of plasticity is more severe in the absence of Ube3a . Furthermore, these data indicate that plasticity defects in Angelman syndrome mice persist into adulthood.

..and so on (go read the full paper)

In a nutshell, what they found was that in presence of visual stimuli, the plasticity (measured by LTP/LTD ) of visual cortex was adversely affected. As sensory stimulus would normally be available while developing, this would adversely affect the plasticity in adolescence/ critical periods and also continue into adulthood.

Thus, Autism/ Angelman are charechterised by less synaptic plasticity in adulthood and during critical development periods. Paradoxically, this loss of synaptic plasticity is concomitant on their it being experience-dependent or having sensory stimuli. If the organism is sensory deprived, it may still retain the normal synaptic plasticity exhibited by similar sensory deprived normal people.

How does this relate to Psychosis? If my thesis is correct that autism and Psychosis are opposites, then I would predict that in either prader-willi or in Psychosis (scheziphrenia etc) there should be excessive experience-dependent plasticity. I was glad to learn that I am not the first one to make that proposition, but someone back in 1995 has argued for Hippocampal synaptic plasticity as an endophenotyoe for Episodic Psychosis. I now quote heavily form that article.

Here is the abstract:

Structural change in the hippocampal formation has become popular as a proposed neurobiological substrate for schizophrenic disorders. It is postulated that behavioral plasticity in the form of long-term potentiation of hippocampal synaptic transmission is an attractive putative mechanism for the mediation of transient psychosis. Moreover, the disturbed hippocampal neuroarchitecture found in schizophrenic brain may be susceptible to potentiation and dysfunctional to the degree that delusions and hallucinations develop. Partial and selective blockade of the receptors mediating potentiation may prove to be an efficient means of preventing psychotic episodes and avoiding further damage to the involved network. Basic research, utilizing experimental models such as intraventricular kainic acid injection, may help to clarify the anatomical and physiological substrate of psychosis.

The Main thesis of the paper is:

1. Anatomical, physiological, pharmacological, and behavioral findings are most consistent with the view that neuropathological changes within the limbic system, specifically within the hippocampal formation, may represent a biological substrate of schizophrenia.

2. The biological mechanism underlying transient psychosis may be long-term potentiation (LTP) of synaptic transmission within the hippocampal formation.

3. The effects of dopamine manipulation on these behaviors may be mediated by direct actions on the compromised limbic system of the psychotic patient.


Associative plasticity within hippocampus occurs in the form of long-term potentiation (LTP), an experience-dependent increase in synaptic efficacy. Experimentally, LTP is produced by tetanic stimulation of afferent systems (Bliss and Lomo 1973) and has been shown to facilitate simple associative learning (Berger 1984) but disrupt more complex forms of associative plasticity (Robinson et al 1989). Hippocampal LTP has been observed to occur as a consequence of stimulus pairings in classical conditioning (Weisz et al 1984) and appears to be mediated by N-methyl-Daspartate (NMDA) receptors (Harris et al 1984). Pharmacological blockade of NMDA receptors has been shown to disrupt learning and memory in a variety of forms, including simple associations (Stillwell and Robinson 1990), spatial learning (Morris et al 1986; Heale and Harley 1990; Shapiro and Caramanos 1990), conditioned fear (Miserendino et al 1990; Kim et al 1991), olfactory memory (Staubli et al 1989) and gustatory memory (Welzl et al 1990). Some evidence, however, suggests that deficits involve motor impairment as well as disrupted learning (Keith and Rudy 1990)

Hippocampal function is particularly sensitive to neurochemical modulation, and the expression of monoamine receptors in the temporal lobe is altered in schizophrenics (Joyce 1993). Antipsychotics that reduce endogenous dopamine levels (Losonczy et al 1987) exert significant effects on the hippocampus and LTP. Trifluoperazine inhibits induction of LTP in hippocampus (Finn et al 1980), whereas the dopamine antagonist domperidone has been shown to prevent the maintenance of LTP (Frey et al 1990). Long-term effects of antipsychotic drugs include functional supersensitivity of hippocampal pyramidal neurons (Bijak and Smialowski 1989). Thus, individuals with deranged hippocampal neuroarchitecture would be prone to cognitive dysfunction (including, perhaps, perceptual distortion and other schizophrenic symptoms), differentially susceptible to stress, and responsive to amelioration of symptoms via dopamine antagonism. It may be more than coincidence that the time lag between administration of antipsychotic medication (which results in near immediate decrement in dopamine levels) and the attenuation of psychotic symptoms weeks later (Kane 1987) is remarkably consistent with the time parameters of LTP decay (Douglas and Goddard 1975). Also, the selective disruption of “weak” associative responses by antipsychotic drugs (van der Heyden and Bradford 1988) is consistent with interactions between NMDA-receptor blockade and stimulation intensity on induction of LTP (Reed and Robinson 1991).

From the above, at least to me, it is clear that anti-psychotics may work by decreasing LTP/LTD that is enhanced in episodic psychosis. A propensity towards increased experience-dependent enhancement of synaptic palsticty may be at work here and paradoxically the same approach of sensory deprivation, as in Angelman/ Autism may work here too.

Here is the summary:

In summary, potentiation of hippocampal synaptic transmission may be the neurophysiological basis of episodic psychosis. (Post [1993] has proposed a similar process in the amygdala as a useful model in understanding the progression of recurrent affective disorders.) More selective blockade of the NMDA receptor, which mediates LTP, may prove an effective means of attenuating positive symptoms and preventing further accrual of cellular damage in hippocampus.

In my own summation, I am convinced that we would find more synaptic plasticity in Psychotic people and that hyper-plasticity to hypo-plasticity is another dimension on which the autistics and psychotics differ and this again is a result of the genomic imprinting mediated tug-pf-war between the maternal and paternal genomes.
PORT, R., & SEYBOLD, K. (1995). Hippocampal synaptic plasticity as a biological substrate underlying episodic psychosis Biological Psychiatry, 37 (5), 318-324 DOI: 10.1016/0006-3223(94)00128-P
Koji Yashiro, Thorfinn T Riday, Kathryn H Condon, Adam C Roberts, Danilo R Bernardo, Rohit Prakash, Richard J Weinberg, Michael D Ehlers & Benjamin D Philpot (2009). Ube3a is required for experience-dependent maturation of the neocortex Nature Neuroscience

Glutamate and classical conditioning

I had speculated in one of my earlier posts that Glutamate , GABA, Glycine and aspartate may be involved in classical conditioning / avoidance learning.  To quote:

That is it for now; I hope to back up these claims, and extend this to the rest of the 3 traits too in the near future. Some things I am toying with is either classical conditioning and avoidance learning on these higher levels; or behavior remembering (as opposed to learning) at these higher levels. Also other neurotransmitter systems like gluatamete, glycine, GABA and aspartate may be active at the higher levels. Also neuro peptides too are broadly classified in five groups so they too may have some role here. Keep guessing and do contribute to the theory if you can!!

Now, I have discovered an article that links Glutamate to classical conditioning. It is titled Reward-Predictive Cues Enhance Excitatory Synaptic Strength onto Midbrain Dopamine Neurons, and here is the abstract:

Using sensory information for the prediction of future events is essential for survival. Midbrain dopamine neurons are activated by environmental cues that predict rewards, but the cellular mechanisms that underlie this phenomenon remain elusive. We used in vivo voltammetry and in vitro patch-clamp electrophysiology to show that both dopamine release to reward predictive cues and enhanced synaptic strength onto dopamine neurons develop over the course of cue-reward learning. Increased synaptic strength was not observed after stable behavioral responding. Thus, enhanced synaptic strength onto dopamine neurons may act to facilitate the transformation of neutral environmental stimuli to salient reward-predictive cues.

Though the article itself does not talk about glutamate, and nor does this Scicurious article  on Neurotopia, commenting on the same , which focuses more on the dopamine connection, still I believe that we have a Glutamate connection here. First let us see how the artifact under discussion is indeed nothing but classical conditioning:

The basic idea is that, when you get a reward unexpectedly, you get a big spike of DA to make your brain go “sweet!” After a while, you being to recognize the cues behind the reward, and so seeing the wrapper to the candy will make your DA spike in anticipation. But it’s only very recently that we’ve been able to see this change taking place, and there were still lots of questions as to what was happening when these changes happen.

So the authors of this study took a bunch of rats. They implanted fast scan cyclic voltammetry probes into their heads. Voltammetry is a technique that allows you to detect changes in DA levels in brain areas (in this case the nucleus accumbens, an area linked with reward) which represent groups of cells firing. So the rats had probes in their heads detecting their DA, and then they were given a stimulus light (a conditioned stimulus), a nosepoke device, and a sugar pellet. There is nothing that a rat likes more than a sugar pellet, and so there was a nice big spike in DA as it got its reward. So the rats figured out pretty quickly that, when the light came on, you stick your nose in the hole, and sugar was on the way. As they learned the conditioned stimulus, their DA spikes in response to reward SHIFTED, moving backward in time, so that they soon got a spike of DA when they saw the light, without a spike when they got the pellet. This means that the animals had learned to associate a conditioned stimulus with reward. Not only that, the DA spike was higher immediately after learning than the spike in rats who just got rewards without learning.

So, if we consider the dopamine spike as an Unconditioned Response, then what we have is a new CS-> CR pairing or classical conditioning taking place. Now, the crucial study that showed that the learning is mediated by Glutamate: (emphasis mine)

To find out whether or not excitatory synapses were in fact changing, they authors conducted electrophysiology experiments in rats that were either trained or not trained. Electrophysiology is a technique where you actually put a tiny, tiny electrode into a cell membrane. When that cell is then stimulated, you can actually WATCH it fire. It’s really very cool to see. Of course all sorts of things are responsible for when a cell fires and how, but what they were looking at here were specific glutamate receptors known as AMPA and NMDA. These are two major receptors that receive glutamate currents, which are excitatory and induce cells downstream to fire. What they found was that, in animals that had been trained to a conditioned stimulus, AMPA and NMDA receptors had a much stronger influence on firing than in non-trained animals, which means that the synaptic strength on DA neurons is getting stronger as animals learn. Not only that, but cells from trained rats already exhibited long-term potentiation, a phenomenon associated with formation of things like learning and memory.

But of course, you have to make sure that glutamate is really the neurotransmitter responsible, and not just a symptom of something else changing. So they ran more rats on voltammetry and trained, and this time put a glutamate antagonist into the brain. The found that a glutamate antagonist completely blocked not only the DA shift to a conditioned stimulus, but the learning itself.

From the above it is clear that Glutamate , and the LTP that it leads to in the mid-brain neurons synapses , is crucial for Classical conditioning learning. Seems that one more puzzle is solved and another jig-jaw piece fits where it should have.

Encephalon Emerald Edition

The emerald Edition of Encephalon is just out at the Neuroscientifically challenged and Marc does a good job of bringing to light some of the most interesting and fascinating posts on brain from the last two weeks. A few that I found immediately drawn to were Greg Downey’s critical appraisal of the neuroplasticity popular press misconceptions and he does a pretty good job of that while simultaneously arousing interest in neuroplasticity in general and Doidge’s book in particular. another goo done is the growing recognition that antidepressant can temporarily increase suicide risk and that anti-psychotics may be a novel treatment for reducing suicide risk as they help control impulsivity. To me dopamine is related to impulsivity and anti-psychotics seem a better bet than anti-depressants when targeting suicide as most suicide is due to high impulsivity. There are many more gems, so go have a look.

TMS causes nurogenesis and LTP in the mice brain!

Transcranial Magnetic Stimulation (TMS) has been shown to be effective in treating depression and schizophrenia , but the exact mechanisms were unknown. TMS is nomally utilized for ‘knocking off’ activity of a brain region near the skull. If this brain area serves an inhibitory function, TMS would lead to more activation in some other connected areas of the brain and vice versa.

As per this blurb from the New Scientist, Battaglia and colleagues found that repeated TMS application to mice hippocampus (dentate gyrus) over a period of 5 days lead to more stem cell neurons there and also lead to strengthening of existing synaptic connection by means of Long Term Potentiation(LTP). It should be noted that hippocampus is one of the prime areas in human brain where neurogenesis happens.

I have blogged earlier regarding the depression-as-low-neurogenesis-in-hippocampus theory and this finding seems to support that theory and provides a mediating mechanism of neurogenesis via which TMS may be leading to alleviation of depression. The researchers also believe that this finding would help in making devices that could lead to alleviation of learning and memory problems like that faced in the Alzheimer’s.

History in the making – the neurogeneisis discovery

There is an old article by Jonah Lehrer in the Seed magazine regarding the historical process via which the fact of neurogenesis in the humna brain was discovered and established.

One of the findings related to the stress/depression and the-lack-of-neurogenesis linkage and the underlying mechanisms that are involved (including sertonergic triggering of cascade reactions that lead to increase in trophic factors). A corollary finding was that enriched environments also lead to more neurogenesis and can help heal the scars formed due to depression/stress by stimulating neurogenesis in the adult brain. How neurogenesis (in areas like hippocampus and dompaminergic neurons) leads to recovery from depression/ stress is still not clear.

To briefly summarize the findings (though it is highly recommended that you read the original article which is very well written):

  1. Neurogenesis happens in adult brains (rats, primates and even humans).
  2. Stress reduces neurogenesis.
  3. Depression and reduced neurogenesis have been found to co-occur.
  4. Enriched environments lead to increase in neurogeneisis. (in rats, marmoset monkeys)
  5. Sertonin-based antidepressants primarily work by increasing neurogeneisis.

Hence inductively it seems probable that Low IQ is caused by Lower SES. (OK, this may seem like a joke…but do go and read the article and Gould’s views on the stress and poverty relationships- and I find her views (and her supporting experimental and observational facts) quite plausible.)

The scientists profiled in the article, at that time, were still wondering (and actively exploring) the exact mechanism between neurogenesis and depression/ stress.

My hypothesis of why depression leads to less nurogenesis in hippocampus would be related to the role of hippocampus in memory and learning and how, for example, repeated exposure to shocks in rats leads the rats to exhibit a phenomenon known as ‘learned helplessness’. Once the memory of a shockful and distressing repetitive experience is entrenched in the rat’s memory, in the hippocampal region, she may not try to explore the environment that much, to discover and learn what has changed regarding the environment, and whether the stressful conditions and environments are over. This may lead to reduced neurogenesis as the rat’s brain resigns itself to fate. This inability-to-learn or ‘learning helplessness’ (my slightly changed term for the same behavioral description) may lead to a vicious downward cycle leading to depression.

Once the neurogenesis is re-triggered, either due to administration of prozac or other antidepressants, or due to Cognitive behavioral therapy (and it had been found using brain scans that these two approaches seem to converge- one working in a top-down fashion (expecations and beliefs), while the other on a molecular and bottom-down fashion ), then the increased neurogenesis leads to an enhanced ability to learn and adapt and thus overcome the depressive epsiode and get rid of the symptoms. In both cases, the brunt of effort to get out of depression is still borne by the individual who is affected.

The other piece of information that caught my fancy was that of the dopimenergic neurogenesis and the potential cure of parkinson’s disease based on targetting this pathway. Whether neurogenisis is limited to hippocampal regions, or also happens in the substatntia nigra/ VTA region (where I guess all the dopaminergic neurons reside) is an important question and my lead to more insight as to which all areas of the brain (or all areas) are susceptible to neurogenesis.

Effect of enriched environments on the brain

Nature Reviews Neuroscience has an interesting article that summarizes the latest findings about neurogenesis and synaptic plasticity in adult mice and how exposure to enriched environments and experience leads to later onset of diseases in transgenic mice models of human diseases like Huntington’s disease, Alzheimer’s disease and Parkinson’s disease, fragile X and Down syndrome, as well as various forms of brain injury.

This is exciting news and lends credence to the fact that for full flowering and upkeep of your mental faculties, mental exercises and stimulating mental environment is a must.

Hat Tip : The Frontal Cortex