Message Board

1. How does this study support the FDA approved use of Risperidone to treat Autistic children ?with mild aggression and explosive behavior without an enduring pattern.? What symptoms of ASD would MPEP be effective in treating?

2. What other behaviors do mGluR5?s play a role in? (Think of what might happen if you agonized these receptors)

3. There are 7 beautiful figures in this study, briefly explain the significance of one of them in your own words (ask me if you need help figuring it out!):
a. Caley Fig 1
b. Clementine Fig 2
c. Drew Fig 3
d. Hannah Fig 4
e. Nick Fig 5
f. Sean Fig 6
g. Zach Fig 7

I thought the study brought up a number of interesting points. The researchers behind the study claims that both Risperidone and MPEP work to treat the repetitive behaviors of the BTBR mice (autism analogs),however, Risperidone had to be given in sedative doses for this effect to be noticed. This suggests that MPEP, an mGluR5 antagonist, might be effective in treating the repetitive and sometimes self-injurious behaviors of those with autism such as the various compulsive behaviors or biting or picking of the skin.

After a little reading up on mGluR5?s, one intriguing possibility I noticed was that it was claimed some antagonists cause memory loss, leading to speculation that an agonist for these receptors could potentially be some sort of smart or memory-enhancing drug. Aside from that, since in the study antagonism of these receptors stopped repetitive movements and behaviors, I would guess that antagonism would induce the opposite, perhaps indicating that these mGLuR5?s have a role in reinforcing certain behaviors such as an Autistic child arranging blocks in a particular, compulsive order.

The portion of the experiment summarized in figure 3 illustrates the researchers? use of the B6 mouse ? a mouse with high sociability and low self-grooming ? as a control for the BTBR mice. Essentially, they administered either saline (a control) or increasing doses of MPEP to the mice and then determined whether they saw an increased sociability based upon if the mouse spent more time in a novel chamber with a novel mouse or a novel object. Graph A shows that these mice did indeed have normal sociability since they preferred the chamber with a new mouse to one with a new object when treated with either saline or MPEP in any dose. Graph B likewise shows that across all treatment groups, the B6 mice spent more time sniffing the novel mouse compared to a novel object. Graph C illustrates that MPEP had no effect on exploratory locomotion, as all treatment groups displayed the same number of entries into the side chambers. Finally, graph D showed no chamber preference in any of the groups. Basically, what this figure illustrates is that MPEP had no effect upon sociability of the B6 mouse, which supports the group?s conclusion that MPEP just reduced repetitive behavior in the BTBR mouse without influencing sociability since the high-sociability B6 mouse did not see any change in its sociability when treated with MPEP.

In this experiment it is shown that Risperidone reduced repetitive self-grooming in mice, though it counteracted by also reducing sociality. It states in the paper "Significant reductions in general locomotor activity following risperidone in BTBR mice are consistent with previous reports in B6 and BALB/c mouse strains". This means that there is less movement from place to place. Reduced movement from place to place may also mean reduced movement in general. If this is true, then it makes sense to say that there would be reduced explosive behavior and aggression as well due to the lack of activity.

It is also said that effects of mGluR5 antagonists can cause effects of amnesia and psychotomimetrics symptoms. Psychotomimetric symptoms are usually found after use of drugs and result in hallucinations and psychosis. It is interesting that Drew says that agonists for the receptor could cause a "smart" drug for this reason. If it can be used to enhance one's memory, it may apply as well to inhibiting drug abuse or used as drug therapy. If someone continually relapses, perhaps agonists of this receptor can be administered and would remove the effects of the drug and help reduce the addiction to the drug.

In Figure 4a, the chart shows that the mouse did not show a change in sociability when administered saline. It spent nearly equal amounts of time interacting with the novel mouse and the novel object, displaying there was no specific effect of saline. In 4b the mouse did not show a change in sociability after being administered MPEP until the dosage was higher than 30mg/kg, in which the mouse did spend more time sniffing the novel mouse. 4c displays the lack of difference in exploration of chambers after the mouse received MPEP, indicating it had no effect on the mouse's sociability. Finally, 4d shows that the mouse did not favor one side or the other during the habituation chamber time. These charts show that BTBR mice do not exhibit sociability and that MPEP did not have an effect on the mouse. The only significance in these mice was that when there was a high amount of MPEP (30mg/kg) the mice sniffed the novel mouse more.

Figure 1 illustrates in an incredibly easy-to-understand format one of the key findings of this experiment. It depicts that while MPEP treatment had no significant affects on the cumulative time B6 mice spent grooming, it significantly decreased self-grooming in BTBR mice when administered in doses equivalent or greater than 1.0 mg/kg. To elaborate, within figure 1A we can see that B6 mice, when treated with MPEP, be it in doses of.5 mg/kg, 1.0 mg/kg, 10 mg/kg, or 30 mg/kg (mg of MPEP/kg of mouse body weight), experienced no alterations in their time spent grooming. However, (figure 1B) BTBR mice who received doses of >1.0 mg/kg of MPEP spent notably less time grooming than the saline BTBR control group. Significance is defined as p< 0.05 when compared to the corresponding saline control. Hence, MPEP has the power to reduce repetitive self-grooming when in high enough doses, and should autistic human subjects follow this model, MPEP could be an effective treatment for reducing the repetitive behaviors which characterize autism.

However, before jumping to such grand, optimistic conclusions, it should be noted that each mouse only received a single drug dose within this experiment. Would long-term treatment maintain the improvement seen in BTBR mice or would the body adapt to the drug treatments, down regulating its effects?

After doing a bit of research, I came across an article on how mGluR5s are necessary for the lateral Amygdala to properly develop fear-based memory (Rodrigues et al., Journal of Neuroscience June 15, 2002). This of course ties directly into our class?s studies of emotions, specifically our discussions on the amygdala as the ?fear center? of the brain. Moreover, mGluR5s are also intricately involved in long-term potentiation in the lateral amygdala. MPEP, a mGluR5 antagonist, was found to reduce symptoms of autism as described in this week?s article. Thus, I?m forced to speculate that many of the emotional abnormalities associated with autism may be related to overactive mGluR5s, particularly those of the amygdala. People with forms of autism often have problems understanding peoples emotions and expressing their own (CDC website). We?ve discussed in lecture that patients with lesions on their amygdala are similarly deficit in understanding emotional content displayed on human faces (specifically fear). mGluR5s could be the link between these two conditions.

Risperidone is a successful second generation anti-psychotic drug developed to treat the negative symptoms of schizophrenia. It?s also approved to treat autistic children who have symptoms of aggression, explosive behavior and self-inflicted injury. In this study, we see that in appropriate doses, BTBR mice showed less self-grooming and less activity in the open field test. This lowering of the locomotor activity does fit risperidone?s action in reducing the aggression and self-injury that occurs in autistic patients. However, I am not convinced that this drug should be approved for autistic patients who exhibit these behaviors only mildly due to several reasons. First, the researchers in this paper pointed out that the lowering of the locomotor activity is only due to the sedative effects of risperidone given at such a dose. I would not be aggressive either if I was sedated. In real autistic children, risperidone decrease their aggressiveness without knocking them out, This gives the first hint that maybe this mouse model doesn?t show the whole drug action of risperidone in humans. Second, this study shows that there is a lowered sociability for the BTBR mice treated with risperidone. However, Risperidone use is known to cause increased sociability in humans with autism, so there is a discrepancy between the animal model and the targeted human group. One possibility I can think of for all this is just due to the difference in brain anatomy. Humans have a much bigger cerebrum structure, and the serotonergic pathways play a more intricate role in our cognitive function. Since Risperidone is mainly a serotonin antagonist, the sum of the drug action could produce the different behaviors in different organisms. Third, for schizophrenic patients, their largest deficit is in their left temporal, frontal lobe of the cortex, and enlarged ventricles due to developmental deficits. These are all areas that play a much larger importance in humans, and if Risperidone treats the deficits in these areas, then perhaps it is harder to see it?s effects on humans by using a lower animals without these areas being as developed as our own. Overall, I don?t think the BTBR mouse model provides a clear enough picture for how risperidone works in autistic patients, in the meantime, use it if it work?

CHPG is an mGluR5 agonist, it potentiates NMDA response in the hippocampus, while one of the side effects of antagonism is amnesia. So that means it could potentially reinforce learning and memory. Antagonism and agonism at selective mGluR5 receptors also provide neuroprotective effects. So perhaps a lack of mGluR5 in certain regions leads to some downstream inflammation that could damage neurons, causing symptoms of autism.

In figure 5A, the researchers are testing for the effect of Risperidone on B6 mice and their self-grooming behavior. B6 is a strain with high sociability and low self-grooming, and BTBR is a strain with high levels of self-grooming, and low sociability. As we can see from the graph, there was no significant difference in the amount of grooming with each increasing dose of Risperidone for the B6 strain. With BTBR mice however, we see a steady decrease in the amount of self-grooming with increasing doses of Risperidone. The importance of these graphs is that Risperidone decreases the amount of repetitive self grooming in autistic mice without lowering that of the B6 which is already low in self-grooming.

As found by this study, risperidone had no affect on sociability in BTBR low-sociability mice, yet it did have the effect of decreasing repetitive self-grooming, analogous to repetitive behaviors in human patients with autism. However, the reason it decreased this behavior was because it had a sedative effect on the mice, effectively drugging them into a kind of stupor; understandably, this did result in decreased self-grooming activity, and indeed any activity at all. In control studies, it was found that mice had no preference for exploration of either of two chambers branching off of the main chamber they were placed in at the beginning of the study; they explored both sides equally. After dosing with risperidone, the mice exhibited little to no exploratory activity. In human patients, it seems that this would correlate to a reduction in aggression and explosive behavior lacking a discernible pattern by causing a complete reduction in overall behavior. The drug is not specific to aggressive behavior, but rather all types, and it shuts them all down equally, producing a generalized sedative effect that, indeed, does reduce explosive outbursts and overall aggression. Unfortunately, in human patients, it does have very similar effects to the mouse analog and does frequently cause sedation, drowsiness, and decreased sexual drive. However, it does what it is advertised to do, hence the approval by the FDA for use to treat the above symptoms. MPEP, on the other hand, both decreases repetitive self-grooming behaviors and does not affect sociability or activity as a whole: it is basically the risperidone without the sedative effect. This seems like it would be pharmacologically useful as a treatment for the repetitive behavior symptoms of autism, however it would not have the same effect on reducing aggression because it does not sedate as risperidone does, which seems to be the primary mode of action employed by that drug to reduce aggression and explosive outbursts.

mGluR5s, after reading the experimental data, appear to by involved in repetitive behavior and its control (since antagonizing the receptors with MPEP reduces repetitive self-grooming in BTBR mice, so it can be assumed that agonizing allows for repetition of such behavior) but not in sociability behaviors nor in the inhibition of aggressive behaviors. Since mGluR5 is a type of glutamate receptor and glutamate is an excitatory neurotransmitter, I would think that it has many of the same effects as other glutamate receptors within the nervous system, such as modulation of long-term potentiation.

Figure 2 in this experimental report depicts the effects of MPEP on both B6 and BTBR mice pertaining to exploration of a novel environment. In B6 mice, which already expressed a low degree of self-grooming and a high degree of sociability, there was not much effect of the MPEP upon their exploration of their environment, though a slight increase was seen with a 30 mg/kg dose of MPEP. In BTBR (low sociability, high self-grooming) mice, however, a very significant increase in activity was seen with increasing doses of MPEP, suggesting that the antagonizing effect of the drug upon the mGluR5 receptors caused them to break free of their cyclic grooming behavior and begin to explore their environment more the more antagonizing effect there was present.

The study is basically a comparison between a less tested drug and an approved drug. The study also seems to focus more on the specific effects of what was observed (reduction in self grooming) vs small observations into socialization and communication deficits. Though, communication would be difficult to measure in mice. However, the major difference between the drugs is the sedative effects of Risperidone. MPEP elicits the same results in a reduction of self-grooming, without a reduction overall activity. However, the sedative effects of Risperidone seem to be the correct choice, not only for autistics with mild aggression and explosive behaviors, but also other psychiatric illnesses. The reduction in self-grooming activity can be seen as almost a side effect; the primary effect being the reduction in aggressive and spontaneous behavior. This effect would be required during phases of outward or inward harm.
The use of MPEP would be to turn the secondary effect of Risperidone into a primary effect. The reduction in Autistic behaviors, notably self grooming. This would be a drug used to treat autism specifically, instead of multiple ailments (or autism-like illnesses).
An interesting thing to note on MGluR5's is that they are part of group 1 receptors. However, all the receptor groups effect memory. Specifically, group 1 effects phospholipase C, which cleaves phospholipids into DAG and IP3. IP3 is a secondary messenger that plays a role in long term potentiation (memory formation and synaptic strengthening). Groups 2 and 3 inhibit cAMP which also play a role in LTP generation. Both of these antagonistic drugs would therefore inhibit LTP generation and possibly LTP maintenance. This is how memory and addiction would be effected by an antagonist. The reduction of LTP would inhibit short term memory formation and inhibit addictive substances from maintaining strong connections. An agonist would instead reinforce these effects, encouraging LTP to create memory faster and increase addiction
Fianlly, Figure 6 is a pretty basic representation of the sedative effects of Ripseridone. Both B6 and BTBR mice showed a reduction in locomotor activity by the admission of the drug. Higher doses elicited a stronger sedative effect on the mice. Interestingly, the B6 mice had a very little effect from the Vehicle delivery device, which contains no drug. The BTBR mice have a strong reduction, suggesting that over time they run out of energy faster than the B6. The highest dose is also a knock-out (not the genetic type of KO). Locomotor activity at .5 mg/kg shows a distance traveled for B6 at nearly zero, while the BTBR are at nearly 100. Perhaps the interation with the autistically effected receptors slightly reduces the sedative effect.

I really enjoyed the point nick brought up about the potential differences in the functionality of Risperidone. I think it is a valid argument that there could be different mechanisms that Risperidone acts on an autistic child's brain as opposed to the brain of an autism model rat. However, like the study stated, the sedative effects of Risperidone seem to be the main reason for decreased self destructive behavior and the excessive grooming in rats. Because of what this study says about the prosocial effects of MPEP on the autism model, as well as the decrease in self-destructive behavior, I think approval of the drug for the treatment of severe autistic behaviour would be beneficial. This behavior could include repetitive movements, self-injuring activities, and lack of exploratory behavior. While this is commonly seen in more extreme cases of autism, I do not see why the drug could not be used for more mild and higher functioning autism cases in lower doses, as the B6 comparison studies showed that MPEP treatment resulted in models becoming about as social as normal mice.

Another role of mGluR5 receptors in conjunction with phospholipase C cleavage is the role of the receptors is a protector against hepatic failure. A study conducted in 2009 showed that by selectively blocking these receptors, using MPEP, resulted in a decrease in the amount and degree of liver damage in mice with lipopolysacharide induced liver failure. Agonizing these receptors might produce the opposite effect. Another study showed that ethanol induced neuropathic pain rats showed a much higher expression of mGluR5 and higher immunoreactivity. I am not sure, but perhaps agonizing these receptors can produce a neuropathic pain response. Interestingly, this theory in conjunction with upregulation of a protein kinase c could explain the generalized increase in in sensitivity seen among the autistic population. (Go Barth LAB!)

Figure 7 uses the B6 mice to show the effect of Risperidone on normal mice as a control. Initially the mice showed a lot of social activity as expected. B) shows a decrease in sniffing time with increases in Risperidone doses, and decreasing sniffing of novel mouse with increasing Risperidone doses. C) showed the decrease in mouse activity with the increasing dose of Risperidone, indicating that it is in fact a sedative. D) is used as a control to show that no side of the chamber was preferred, eliminating the posibility that this could have affected the results of activity and social interaction.