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Metabotropic glutamate receptor 5 (mGluR5) shows differential associations with NMDAR NR2A and NR2B subunits in schizophrenia: implications for novel mGluR5 therapeutics

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12th Biennial Australasian Schizophrenia Conference, Melbourne, Australia, May 13-14 2013

Newell K.1, 2, Matosin N.1, 2, Geddes A.1, 2, Frank E.1, 2, Huang X.F.1, 2

1 Centre for Translational Neuroscience, IHMRI, University of Wollongong, NSW 2522. 2 Schizophrenia Research Institute, Sydney.

Background: Metabotropic glutamate receptor 5 (mGluR5) has been identified as a promising therapeutic target for schizophrenia, predominately due to its physical and functional interactions with the glutamatergic NMDA receptor (NMDAR). However, it remains unclear whether mGluR5 or the mGluR5/NMDAR complex is altered in schizophrenia. This is crucial information that may impact the efficiency of novel mGluR5-based therapeutics.

Objectives: We aimed to determine whether mGluR5 binding or protein densities were altered in schizophrenia, or if there were differential associations between mGluR5 and the NMDAR, including NR2A and NR2B NMDAR subunits, in schizophrenia and control subjects.

Methods: Using in situ radioligand binding and immunoblot, we measured [3H]MPEP binding to mGluR5 and mGluR5 protein density in the post-mortem dorsolateral prefrontal cortex (DLPFC) of 37 schizophrenia subjects and 37 matched controls. Additionally we measured [3H]MK-801, [3H]CGP-39653, and [3H]Ifenprodil binding to total NMDARs, NR2A-containing NMDARs and NR2B-containing NMDARs respectively. We further assessed NMDAR NR2A and NR2B subunits with immunoblotting. Statistical approaches were used to determine associations between mGluR5 and NMDAR(total)/NR2A/NR2B.

Results: mGluR5 binding and protein expression were not significantly altered in the DLPFC of schizophrenia subjects compared to controls. However, mGluR5 binding and protein were significantly associated with NMDAR binding and protein in schizophrenia subjects (but not controls); mGluR5 binding was positively associated with NMDAR(total) binding (using [3H]MK-801; r=+0.489, p=0.002) as well as NR2B binding (using [3H]ifenprodil; r=+0.355, p=0.031). In contrast, mGluR5 binding was negatively associated with NR2A binding (using [3H]CGP-39653; r=-0.413, p=0.012). These findings were supported by immunoblotting analyses in the same tissue.

Conclusions: These findings suggest that mGluR5 expression is not altered in schizophrenia, indicating that mGluR5 is an unimpeded target to modulate NMDAR activity in schizophrenia. However, our findings show differential associations between mGluR5 and NR2A- versus NR2B-containing NMDARs in schizophrenia, which may have functional implications for mGluR5-targeted therapeutics in these patients.

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Negative findings with positive consequences: a discussion of publication bias and the impact conundrum

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February 28, 2013. Over time, there has been pressure on scientists to choose investigative avenues which result in high impact knowledge. In fact, the pressure and competition of  research output has swayed scientists in the past to fudge their results. Whilst I am not justifying this behaviour, I understand that it stems from an ever-heightening hurdle that scientists need to jump – high publication output with high citation rate in order to win competitive grants and awards to drive the research, move up the rungs and pay the bills. Published a few years ago in PLOS ONE, Daniele Fanelli states that “Papers are less likely to be published and to be cited if they report ‘negative’ results“. Furthermore, journals of higher qualities and impacts might as well have a bold statement in the submission form, negative results are not accepted. I’m not sure if you’ve noticed, but there seems to be a gap here between results which are positive and results which are high impact. I don’t see the connection, but scientific culture has assumed that they equate each other. Why can’t negative results be of high impact?

A short time ago, a research paper that I first-authored was accepted for publication (read here). Building on from this study, I also presented some data at the Australian Neuroscience Society Conference in Melbourne last month (read here). Collectively, my research and that of Elisabeth Frank has shown that across three post mortem cohorts, the brain proteins mGluR2/3 and mGluR5 are NOT altered in the prefrontal or anterior cingulate cortices in schizophrenia, with the latter study further demonstrating the same outcome in bipolar and major depression – disorders which commonly overlap with schizophrenia diagnosis.

If you’re not familiar with metabotropic glutamate receptors, or mGluRs, they are G-protein coupled receptors that modulate the activity of fast signaling receptors such as the NMDA receptor (which is believed to be dysfunctional in schizophrenia – see Weickert et al., 2012, or my previous post). In particular, mGluR subtype 5 (mGluR5), which is the subject of my PhD thesis, is known to have some control over NMDA receptor activity. For this reason, developing drugs to either enhance or reduce mGluR5 function have become of interest (for more detail, read this).

However, because previous animal studies have shown that blocking mGluR5 can cause schizophrenia related behaviours, it caused speculation that maybe mGluR5 expression is altered in schizophrenia. So we looked into it.

As can be seen from the data we recently published, we found that, against our initial hypothesis, mGluR5 expression was not affected in people with schizophrenia (read here). This confirmed the results of previous studies, but in a larger cohort. And so our hypothesis was now that mGluR5 expression was not altered after all. We then did a follow up study to confirm this was also the case in other neurological disorders as comorbidity is common in schizophrenia, and found the same thing. So now, we have results from three post mortem cohorts (collectively 52 patients with schizophrenia, and 39 with depression), which show, in line with our hypothesis, that mGluR5 expression is unchanged – pretty solid in my opinion.

If you approach these results from the perspective of uncovering the underlying cause of schizophrenia, then yes, these results are negative – mGluR5 doesn’t seem to be involved. But my project is a bit more unusual than this, because despite that this protein is not altered, it is linked to something which probably is. This gives it a unique property – it is an unhindered target with the ability to correct glutamate signaling. What I mean, is that if mGluR5 modulators, which have been shown to reverse schizophrenia-related symptoms in preclinical models, are not changed in schizophrenia, its actually a GOOD thing because the therapeutic target is present. If mGluR5 was reduced, then there may be problems with the efficacy of the drug in the pathological state.

Ok so that’s the background to this blog post. Not an issue… until I tried to publish and publically present the data.

We received two rejections from higher impact journals in response to the paper, and some cynical feedback after the oral presentation concerning being defensive and creatively concocting a narrative to re-angle the negative findings. It begun to make me wonder… why is a negative finding viewed as such a bad thing? And what did those comments even mean? “Oh too bad, you lost the protein lottery and chose one which isn’t changed”? Were they suggesting to not publish the data? This really threw me off, because I thought that right and wrong were opinions, and as scientists it was our sole duty to report the facts.

A little curiosity triggered some light investigation (the most predictable behaviour of a researcher) and I found out that this has been a common theme in the history of science (see Publication Bias). In fact, it reached the point of a journal specifically created to publish the ‘rejects’: The Journal of Negative Results. Then I came across this comment published in Nature: “… negative findings are still a low priority for publication, so we need to find ways to make publishing them more attractive.” That’s a beauty. And perfectly explains what I’m trying to get across.

Negative findings can have positive outcomes. As Nicholas Parrish quoted, “Imagine a meticulously edited, online-only journal publishing negative results of the highest quality with controversial or paradigm-shifting impact. Nature Negatives.” Negative results are taboo, but sometimes Support for the Null Hypothesis can still have extensive implications which are worthy of publication, and in my case, real clinical relevance which can be translated to other fields of medicine, pharmacology and biology.

My question is, why is it a negative finding anyway? It seems overly philosophical to me. A negative result is in response to a positive question. If you rephrased to a negative question, does that mean you have a positive finding? Fuel for thought.

So, while I’ve been accused of ‘being too close to my data’, ‘spinning a story out of nothing’, ‘expecting a change and didn’t find one’, I tend to disagree. At the core, we are scientists, and it is our duty to both 1) publish all data, no matter the outcome, as a negative finding is still an important finding (in my case, a favourable finding), and hence 2) we need to have a theory to explain the finding. If we performed the experiment to plan, we haven’t manipulated our data to pull something out of context, and we have solid evidence of a negative result, then it is our duty to explain why we are seeing what we are seeing. It does not, in my opinion, mean that it is making a story out of dust, that the results are any less important, or that the results should go unpublished.

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NMDA receptor hypofunction in schizophrenia – elusive no longer?

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Brains1 November 2012. The NMDA receptor is one of the most highly implicated receptors in schizophrenia development and pathophysiology. Despite this, post mortem studies examining the NMDA receptor have been inconclusive, with various reports showing increases, decreases and no change across the various NMDA receptor subunits.

Recently, however, a collaborative effort across the Schizophrenia Research Institute’s laboratories, led by the Weickert group, have corroborated that the NMDA receptor is altered in schizophrenia.

Using techniques across molecular neuroscience and psychological disciplines, leading schizophrenia researchers Cyndi and Tom Weickert have led a study to analyse alterations in NMDA receptor subunits at the genetic, mRNA, and protein levels within the dorsolateral prefrontal cortex (a brain region with cognitive functions) of post-mortem schizophrenia brains, as well as correlating this with cognitive function in antemortem patients with schizophrenia.

In the largest post-mortem cohort to date, this comprehensive study has reported alterations across the various levels of transcription in a number of NMDA receptor subunits, suggesting that the NMDA receptor may, after all, be altered in schizophrenia sufferers.

How did they test it?

To get a true understanding of how the NMDA receptor might be altered in the schizophrenia brain, Weickert and team studied the NMDA receptor subunits at various translation levels in the dorsolateral prefrontal cortex of schizophrenia subjects and matched controls. mRNA transcripts were measured for NR1, NR2A, NR2B, NR2C and NR3A subunits of the NMDA receptor, and this was supplemented with NR1 protein levels.

The NMDA receptor itself is complex in nature, consisting of two obligatory NR1 subunits accompanied by a combination of two NR2 (NR2A-D) or NR3 subunits (NR3A and B). Alterations in the NR1 subunit may be thought as the most detrimental, as the NMDA receptor cannot survive without it. In light of this, the most exciting result was that both NR1 mRNA and protein were reduced in the dorsolateral prefrontal cortex of subjects with schizophrenia, strongly suggesting that NMDA receptor levels are reduced in schizophrenia pathophysiology.

An additional finding of decreased NR2C mRNA suggests that there may be alterations in receptor composition. As NMDA receptor composition is indicative of function, this could have implications for NMDA receptor-related signalling. However, it should be noted that altered mRNA levels do not necessarily translate to alterations of protein (see Greenbaum et al., 2003). Since NR2C protein was not measured in the present study, this remains to be speculation.

A handful of NMDA receptor SNPs that had previously been associated with schizophrenia were also analysed to complete the picture. These SNPs were then correlated with antemortem measures of cognitive function. The minor C allele of the NR2B gene SNP rs1805502 was associated with lower reasoning ability in patients with schizophrenia, and this also correlated with reduced levels of NR1 mRNA and protein in the dorsolateral prefrontal cortex. This signifies an intricate relationship between NMDA receptor subunits, across various levels of protein translation, and suggests that perhaps this is unbalanced in schizophrenia pathology.

NMDAR

NR1 mRNA and protein is reduced in subjects with schizophrenia.

A small article but a big step forward.

The NMDA receptor has long been implicated in the pathophysiology of schizophrenia. In 1980, Kim et al. first put forward that glutamate levels may be altered in schizophrenia when they found decreased glutamate levels in the cerebrospinal fluid of schizophrenia sufferers.

This was later supported by studies showing that pharmacological blockade of the NMDA receptor caused psychotic symptoms in healthy people that are so alike to schizophrenia that it is often difficult to distinguish (see Javitt et al., 1991; Krystal et al., 1994; Lahti et al., 1995). The same treatment also significantly intensified the pre-existing symptoms of schizophrenia sufferers.

Hence, the glutamatergic system subsequently came under scrutiny by researchers.

Stemming from these studies, the NMDA receptor hypofunction hypothesis posits that dysregulation of glutamate is caused by NMDA receptor hypofunction on neurons of GABA subtype in subcortical regions. This leads to disinhibition of glutamatergic efferents destined for the cortex, causing a hyperglutamatergic state (see Marek et al., 2010). This theory is powerful, as it appears to account for all schizophrenia symptom profiles (positive, negative and cognitive).

It should be noted that although the NMDA receptor is widely implicated in glutamatergic dysfunction, it is unlikely that it is the solitary aetiological factor. Still, evidence suggests that many schizophrenia risk factors converge on the NMDAR rendering it of primary concern (see Kantrowitz and Javitt, 2010).

Therefore, the reductions of NR1 subunits reported by the Weickert team are in line with the glutamatergic hypothesis, providing compelling evidence that NMDA receptors are down regulated to accommodate for excess glutamate levels in the cortex. Hence, the manifestation of schizophrenia symptoms, especially cognitive dysfunction (as demonstrated in the antemortem findings of the present study), probably hinge on the NMDA receptor.

As cognitive dysfunctions remain largely untreated by current pharmacotherapies in many patients with schizophrenia, this study endorses the pursuit of novel therapeutics to reverse NMDA receptor hypofunction in the cortex of schizophrenia sufferers.

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Reference: Weickert CS, Fung SJ, Catts VS, Schofield PR, Allen KM, Moore LT, Newell KA, Pellen D, Huang XF, Catts SV, Weickert TW. Molecular evidence of N-methyl-D-aspartate receptor hypofunction in schizophrenia. Mol Psychiatry. 2012 Oct 16.

To read this article, visit: http://www.nature.com/mp/journal/vaop/ncurrent/full/mp2012137a.html

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Preclinical breakthrough in potential therapeutics for schizophrenia

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Promising new mGluR5 PAMs, LSN2463359 and LSN2814617 – a step closer to clinical trial?

13 October 2012. Positive modulation of metabotropic glutamate receptor 5 (mGluR5) has been posited to reverse all aspects of schizophrenia symptoms due to their ability to up-regulate NMDA receptor (NMDAR) activity. A collection of studies recently released from a collaboration between Eli Lilly and Cambridge University in the UK have described in vitro and in vivo properties of two novel mGluR5 potentiators, LSN2463359 and LSN2814617, which display antipsychotic effects for the potential treatment of schizophrenia.

In an analysis of both in vitro and in vivo techniques, scientist Mark Tricklebank of the Eli Lilly laboratories led an investigation that characterized the potential of these agents across motor, instrumental and cognitive paradigms.

mGluR5 has been of interest for some time due to its ability to increase the activity of the NMDAR, a protein which is proposed to be under-active in schizophrenia. Despite the theory, shortfalls of these agents have caused them to fall behind PAMs of their cousins mGluR2/3, which have progressed into clinical trials. Now, it seems that key issues such as oral bioavailability, sedative effects and intrinsic agonist activity have been overcome.gilmour pic

Preliminary, although extensive, evidence suggests that these two novel PAMs surpass their earlier counterparts CDPPB and ADX47273 in many areas. The two Lilly compounds are shown to be potent and selective potentiators of mGluR5, and have shown promise for the treatment of negative and cognitive aspects of schizophrenia symptomatology, which are largely untreated by current antipsychotic agents.

The properties broken down

To understand the value of these Lilly compounds, first author Gary Gilmour first tested the properties of these drugs on cell cultures from both rats and humans – that is, neurons grown outside of the body. Using a range of techniques, Gilmour was able to compare a number of pharmacological properties with the older mGluR5 PAMs, CDPPB and ADX47273. It was confirmed that the Lilly compounds did not behave as agonists, which is important as this meant the drugs would work in synchronization with the normal cell signaling rather than having harsh effects on the neuron. Also, it reduces the chances of receptor desensitization over time.

Next, they checked how specific the drugs were, in order to confirm that they were not binding to sites except the ones they were intended for. They were tested against agonists, potentiators and antagonists of mGluR1-4, mGluR8 and GABAB receptors, which are all G-protein coupled receptors with similar functions to mGluR5. However, they found that both LSN2463359 and LSN2814617 were selectively and strongly binding to mGluR5 only.

In addition to the binding mechanisms, one of the most important factors to test was that when the Lilly compounds were given orally, that they would be able to make their way to the brain and significantly bind and occupy the mGluR5s. This was tested both in vitro and in vivo, with very high occupancy found for both compounds (the latter measured in the rat hippocampus). This is far superior to previously described mGluR5 PAMs, none of which have been able to be dosed orally. In terms of both the preclinical and clinical future of the Lilly compounds, this is an enormous advantage.

The behavioural outcomes

Once the pharmaceutical properties of LSN2463359 and LSN2814617 were recorded, the drugs were then tested in animal models to see if they were able to have a therapeutic effect. The rats were given doses of amphetamine to induce hyperlocomotor behaviour, which is a preclinical test representative of positive schizophrenia symptoms. The Lilly compounds were compared with haloperidol, CDPPB and ADX47273 in their ability to reverse hyperlocomotion.

None of the mGluR5 PAMs (including the Lilly compounds) came close to the typical and long-used antipsychotic haloperidol. Despite that the Lilly compounds and CDPPB had some effects at some doses, it was much less than for haloperidol, with ADX47273 showing no effect at all. This new data suggests that mGluR5 modulation may not be useful for positive symptoms in schizophrenia, which has been long believed.

The authors subsequently measured the wake promoting effects of the Lilly compounds, as a problem with current antipsychotics is that they have sedative effects in many patients. They found that these compounds increased wakefulness in the animals, and suggested that this is probably because they have higher levels of receptor occupancy. They also suggested that this could be due to their connection to Homer1, which has previously been linked to sleep/wake behaviours.

Lastly, the Lilly compounds were examined to test their ability to reverse deficits in two tests of operant behaviour, i.e. the ability to change behaviour based on the environment. To test visuospatial working memory, the drugs were administered and then the rats underwent the delayed match to position task (DMTP). The authors found that the drugs had effects on visospatial working memory at some doses, but overall there was no effect. They thought this may be due to the wake-effects of the drugs, so they teased this effect out experimentally but still found no change. However, in the second test of instrumental responding, both Lilly compounds reversed deficits induced by NMDAR antagonists at the same therapeutic doses that were shown to cause beneficial arousal effects.

Is that it? What’s next?

These are promising results for a much-needed development in the area of mGluR5 PAMs for the treatment of schizophrenia. Despite the positive results regarding in vitro characterization, more studies are required to decipher the lack of effect for reversing amphetamine-induced hyperlocomotion and what appears to be a minimal effect in one test of operant behaviour. Nonetheless, the oral administration route, in combination with the wake-promoting effects and ability to attenuate some deficits induced by NMDAR antagonism, is encouraging.

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Reference: Gilmour G, Broad LM, Wafford KA, Britton T, Colvin EM, Fivush A, Gastambide F, Getman B, Heinz BA, McCarthy AP, Prieto L, Shanks E, Smith JW, Taboada L, Edgar DM, Tricklebank MD. In vitro characterisation of the novel positive allosteric modulators of the mGlu(5) receptor, LSN2463359 and LSN2814617, and their effects on sleep architecture and operant responding in the rat. Neuropharmacology . 2013 Jan ; 64(1):224-39.

To read this article, visit: http://www.sciencedirect.com/science/article/pii/S0028390812003668

Metabotropic Glutamate Receptors 2/3 and 5 in schizophrenia and allied mood disorders: evidence supporting mGluR-based therapeutics

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12th Biennial Australasian Schizophrenia Conference, Melbourne, Australia, May 13-14 2013.

Matosin N.1, 2, Fernandez F.1, 2, Frank E.1, 2, Deng C.1, 2, Wong J.1, 2, Huang X.F.1, 2 and Newell K.A.1, 2

1 Centre for Translational Neuroscience, IHMRI, University of Wollongong, NSW 2522. 2 Schizophrenia Research Institute, Sydney.

Background: Metabotropic glutamate receptors (mGluRs) are proposed novel therapeutic targets for schizophrenia and mood disorders. Despite this, the binding potential of mGluRs in these disorders remains uncertain. This information is crucial to understand the efficiency of drugs that target these receptors.

Objectives: To determine the binding profile of mGluR2/3 and mGluR5 in schizophrenia and related mood disorders.

Methods: Using post-mortem human brains from the Stanley Neuropathology Consortium (schizophrenia [SZ], major depression [MD], bipolar disorder [BP] and control [CT]: n=15/group) and Depression Collection (major depression [MD], major depression with psychosis [MDP], CT: n=12/group), mGluR2/3 and mGluR5 binding densities were measured in the anterior cingulate cortex by in situ receptor autoradiography.

Results: Whilst preliminary analyses indicated no diagnostic effect on mGluR2/3 or mGluR5 binding densities, a number of differential age effects were observed. mGluR2/3 negatively correlated with age in CT (Neuropathology Consortium: r=-0.695, p=0.004; Depression Collection: r=-0.765, p=0.063), SZ (r=-0.528, p=0.043) and MDP (r=-0.765, p=0.006) subjects but not BP or MD (both Neuropathology Consortium and Depression Collection). Conversely, mGluR5 showed significant or borderline-significant positive associations with age in SZ (r=0.505, p=0.055), MDP (r=0.551, p=0.090) and MD (Neuropathology Consortium: r=-0.453, p=0.090; Depression Collection: r=0.587, p=0.045) subjects, but not CT or BP.

Conclusion: Targeting mGluRs may provide a therapeutic mechanism to modulate glutamatergic activity in psychiatric disorders. Therefore, unaltered levels of mGluRs in SZ, BD, and MD are beneficial as they suggest unimpeded therapeutic targets. However the association between age and both mGluR2/3 and mGluR5 binding may have age-dependent therapeutic implications for the use of these drugs in some patients. There are no published investigations examining mGluR function in these disorders, which may be integral to interpreting absence of change in mGluR protein levels, and the potential of mGluR-based therapeutics.

Final ASC poster

Lost in the details.

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ripple_effect

March 12, 2013.  Medical research is a lot like a ripple – there is a core problem, causing effects that are transferred outwards in concentric circles. Occasionally we may endeavour to put the problem in perspective. More usually, however, we are so focused on what caused the ripple that we forget to look at the bigger picture.

When studying a complex neuropsychiatric disorder like schizophrenia, it is easy to get lost in the details. All the little molecular alterations and effects, interacting together like rain drops on the surface of a pond. But while the details may be where the answers lie, the big picture helps to drive us forward.

Ashley is close to my age, and she suffers from paranoid schizophrenia. She writes a blog, “Overcoming Schizophrenia”, where she is open about her illness and her quest to overcome it. I have found Ashley incredibly inspiring, and listening to her story reminds me of why we continue research into the underpinnings of schizophrenia. I encourage you all to listen to her story and be inspired by Ashley as well.

Concepts to Credibility

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Business model of a scientist

March 10, 2013. An idea that I have been throwing around for a while is that scientists are businesses. I’m not talking about scientists going into industry or commercialising research. I mean that we ourselves are a business – we are a company (the investigator) who offer a service (research) to a market (institutes, universities and industries), and trade our goods (skills, techniques and expertise) in return for profit (publications, funding, credibility and reputation – the research currency). When you consider that the fundamentals of science are intrinsically linked with innovation, it is not a far reach to conceptualize that scientists run their careers like a business.

I have never considered myself a business-minded person. In fact, the thought of any commerce-related subject makes me cringe (no offence). But as my husband, parents and close friend run their own businesses, I have often found myself in the associated conversations.  Somewhere along the way, it clicked that many of the concepts that we’ve discussed concern me too… for example, getting yourself out there, finding your niche, and weighing up opportunities. It made me realise that scientists are in-house businesses.

This was reinforced for me a few weeks ago. I attended a presentation by John Bell of Zen Media, Sydney, who deals with increasing revenue for small businesses. When I started listening to the talk, there were words being thrown around like ‘promoting’, ‘selling’ and ‘pitching’. I straightaway thought the talk would be irrelevant, and that it was aimed at the commerce-based people in the room. Then I started to really listen.

‘What is the value of your work?’ … um, H-index.

‘Have you explained, convinced and persuaded that your idea is excellent?’ Grant writing.

‘Have you differentiated yourself, and thought about what gives you the advantage, and how you will maintain and protect it?’ Sounds an awful lot to me like applying for a fellowship.

And that was the point where I started taking notes.

Like a business, scientists need to sell their ideas and expertise. We see that there is an opportunity with potential (research question), and then we formulate a plan (research project) to act on it. We explain that there is a problem that needs solving and that WE have the keys to do it. Then we provide an innovative solution to a problem that will be valuable to some aspect of society.

But developing an idea into an opportunity and subsequently into a success requires funding. Applying for funding is analogous to a business pitching to an investor. Will they entrust you to deliver? Are you the person they should give their money to? Can you convince them that you are the best person to do the job?

Come to think of it, the art of writing a grant is much like the art of writing a business plan. You need to build a logical story and have well-reasoned steps to prove that you will achieve your outcomes. And like a business, it’s all about differentiating yourself – what makes you different? What gives you the advantage? How do you plan to maintain and protect it? You’re a detective who needs to collect skills and expertise as you go to ensure you have the knowledge and the tools to uncover the answer to your problems.

And then built on this, if you are the lucky one who makes it, you also have the physical business to run – your laboratory. The business related duties here are endless: project management, people management, finance management, and strategic planning, just to name a few.

As I said before, I’m not particularly interested in business or entrepreneurial studies, but I have to admit that some of the parallels are quite interesting. Whilst our achievements are ranked by peer-reviewed publication, it is synonymous with the profits that define the success of a business.

Both science and business are competitive worlds, and I think they overlap in each scientist. Researchers may do well to search within themselves to discover new avenues for growth and ways to expand their core business, in order to truly reap the benefits of their research.Business plan of a grant

An analysis of metabotropic glutamate receptors 2/3 and 5 in schizophrenia, major depression and bipolar disorder from the Stanley Neuropathology Consortium

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ORAL-11-07, Australian Neuroscience Society 33rd Annual Meeting, Melbourne, Australia, February 3-6 2013.

Matosin N.1, 2, Frank E.1, 2, Fernandez F.1, 2, Deng C.1, 2, Wong J.1, 2, Huang X.F.1, 2 and Newell K.A.1, 2
1 Centre for Translational Neuroscience, IHMRI, University of Wollongong, NSW 2522. 2 Schizophrenia Research Institute, Sydney.

Purpose: Metabotropic glutamate receptors (mGluRs) are proposed novel therapeutic targets for a variety of brain disorders such as schizophrenia (SZ), bipolar disorder (BP) and major depression (MD). Despite their potential, the involvement of these receptors in these pathological processes is uncertain. This information is crucial to understand the efficiency of drugs that target these receptors. Methods: Using post-mortem human brains, mGluR2/3 and mGluR5 binding densities were measured in the anterior cingulate cortex of SZ, BP, MD and matched controls (CT) (n=15/group) by receptor autoradiography. Results: Whilst preliminary analyses indicated no diagnostic effect in mGluR2/3 or mGluR5 binding densities, mGluR2/3 binding negatively correlated with age at death in the CT (r=-0.695, p=0.004) and SZ (r=- 0.528, p=0.043) groups, but not MD or BP. Contrarily, mGluR5 displayed a borderline positive correlation with age at death in SZ (r=0.505, p=0.055) and MD (r=-0.453, p=0.090) subjects. Furthermore, mGluR2/3 and mGluR5 binding correlated in subjects with SZ (r=-0.516, p=0.049), but not BP, MD or CT groups. Conclusion: Targeting mGluRs may provide a therapeutic mechanism to modulate glutamatergic activity in psychiatric disorders. Our findings of unaltered levels of mGluRs in SZ, BD, and MD may be beneficial by potentially providing an unhindered therapeutic target. However the association between age and both mGluR2/3 and mGluR5 binding in SZ subjects may have age-dependent therapeutic implications for the use of these drugs in SZ patients. There are no published investigations examining mGluR function, which may be integral to interpreting absence of change in mGluR protein levels.

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Metabotropic Glutamate Receptor Subtype 5 is Reduced in Schizophrenia Subjects with Comorbid Major Depression and Unchanged Following Antipsychotic Drug Treatment

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Australian Neuroscience Society 32nd Annual Meeting, Queensland, Australia, January 29-February 1 2012.

Jimenez N, Huang XF, Deng C, Newell KA.

Purpose: To examine mGluR5 expression in the dorsolateral prefrontal cortex (DLPFC) of schizophrenia subjects compared to control subjects. Additionally, to investigate whether antipsychotic drug (APD) treatment causes adaptive changes in mGluR5. Methods: Using post-mortem human brain tissue, mGluR5 binding and protein density were measured in the DLPFC of schizophrenia subjects (n=37) and matched control subjects (n=37) using autoradiography and western blot methods respectively. Subsequently, rats treated with haloperidol, olanzapine or vehicle, for short-(8 days), medium-(15 days) or long-term (35 days) durations (n=6/group) were tested for alterations in mGluR5 binding levels in the PFC by receptor autoradiography. Results: Subjects comorbid with major depression (the majority of which suffered schizoaffective disorder) displayed a 31% decrease in mGluR5 binding density (p=0.014). mGluR5 protein level was unaltered. mGluR5 did not correlate with pre-mortem APD or antidepressant treatment. Finally, mGluR5 binding was unaltered in the PFC of APD treated rats. Conclusion: This study found reductions in mGluR5 binding in the DLPFC of schizophrenia subjects, specifically in those with comorbid major depression. However, as protein levels were unaltered, this suggests a possible alteration in receptor function rather than receptor numbers. This study highlights that alterations in mGluR5 receptors vary with symptomatology/comorbidity , which is paramount information to include in future studies. In addition, this study points towards a role of mGluR5 as a pharmaceutical target for the treatment of schizophrenia, at least in cases of specific symptoms associated with subdiagnosis and comorbidity, especially as it was found in this study that current therapeutics do not influence mGluR5.Natalie Jimenez ANS 2012 poster