“Type 3” Diabetes in Alzheimer’s, but maybe also in some Autism

Intranasal insulin, for cognitive enhancement in Alzheimer’s and …

Today’s post was sparked by another little experiment of mine; no, not intranasal insulin.

Recently I have been using a reduced number of therapies on Monty, aged 12 with ASD.  Some people think there are just too many pills.

I wrote many posts last year about something called PPAR gamma (Peroxisome proliferator-activated receptor gamma, PPAR-γ or PPARG, also known as the glitazone receptor).

As you can read in Wikipedia:-

PPAR-gamma has been implicated in the pathology of numerous diseases including obesity, diabetes, atherosclerosis, and cancer. PPAR-gamma agonists have been used in the treatment of hyperlipidaemia andhyperglycemia. PPAR-gamma decreases the inflammatory response of many cardiovascular cells, particularly endothelial cells. PPAR-gamma activates the PON1 gene, increasing synthesis and release of paraoxonase 1 from the liver, reducing atherosclerosis.

Many insulin sensitizing drugs (namely, the thiazolidinediones) used in the treatment of diabetes target PPARG as a means to lower serum glucose without increasing pancreatic insulin secretion.

What we found out in earlier posts that PPAR-gamma can be used to reduce microglial activation, which should turn down the body’s “immunostat”.  A key feature of many people’s autism appears to be an over-activated immune system, reflected by activated microglia.

PPAR-gamma agonists as regulators of microglial activation and brain inflammation.

The present review summarizes the several lines of evidence supporting that PPAR-gamma natural and synthetic agonists may control brain inflammation by inhibiting several functions associated to microglial activation, such as the expression of surface antigens and the synthesis of nitric oxide, prostaglandins, inflammatory cytokines and chemokines. 

Although most of the evidence comes from in vitro observations, an increasing number of studies in animal models further supports the potential therapeutic use of PPAR-gamma agonists in human brain diseases including multiple sclerosis, Parkinson's disease and Alzheimer's disease.

Experiment

The potent PPAR-gamma agonist drugs like Rosiglitazone, have side effects which I think make them unsuitable for autism.  I use a flavanol called Tangeritin, in the form of a supplement called Sytrinol.

For two months we have not used Sytrinol, but yesterday Monty had one pill after lunch.

The piano lesson was great and then Monty had three hours with his Assistant, doing academic work and then some more piano practice.

Before she went home, Monty’s Assistant spent ten minutes telling me, and Monty’s big brother, just how great the afternoon had been.

“Monty was amazing today”

“When he was doing math, it was like he wasn’t autistic”

(we live in a country where autism means strict definition autism, what in the US is called severe autism)

“Did you hear how he played the piano?”

I told Monty’s brother to make a mental note of this and tell it to Mum/Mom later.

The next day the effect of Sytrinol was not as profound.

This actually is a recurring theme, the effect of various interventions is the greatest at the beginning  and then, as the body’s feedback loops get involved, the effect reduces.  

The same is true with cinnamon, another food-based intervention, that also helps people with diabetes.  The effect in (some) autism is greatest when you start.

It would be great if it was possible to keep the full initial effect of both Sytrinol and Cinnamon, and avoiding the dampening reaction caused by feedback loops.

I think if this is possible, it will be via targeting the therapy directly at the brain, rather than the entire body.  This can be achieved via the intranasal route, as used with oxytocin.

What to put in the spray?  This would be a very personalizable solution, since different people have different dysfunctions and to varying degrees.  Some possibilities might include:-

·        Insulin  (read on to learn why)
·        IGF-1
·        T3 thyroid hormone
·        TRH
·        Type 2 iodothyronine deiodinase (D2) 
·        Oxytocin
  

Fine tuning Cognition

It is difficult to be certain what therapy is responsible for what effect.

I recently told one researcher/parent that interventions in autism seem to take effect very quickly and so you can pretty rapidly run through a series of mini-trials to see what helps, what makes things worse and what does nothing.  Being a researcher, his view is that you need to try things for much longer.

One problem of trials lasting months is that external factors may then change, that cause behavior to change and distort the result. This is why I try to avoid trials from May to October, the allergy season.

Many people do find that some supplements help a lot for a week or two and then make things worse.  This includes things like some B vitamins and carnitine.  For other people continued use keeps giving a positive effect.

Previous Experience with Sytrinol

Monty’s assistant at school last year thought Sytrinol made him cleverer.

She also thought the PAK inhibiting propolis (BIO 30) had a similar effect.  This propolis is quite expensive and I concluded the effect was small and this might be because it just was not potent enough. 

One reader of this blog is using a much more potent PAK inhibitor, FRAX486, and some people in the US use Ivermectin.

Ivermectin is an anti-parasite drug which also happens to be a PAK inhibitor.  It is not suitable for long term use.

 Why would Sytrinol improve cognition?

I have written a lot about PPAR gamma in the past, so today has a new angle on the subject.

I did a quick check on PPAR gamma and cognition.

I was surprised what I found.

  

Central activation of PPAR-gamma ameliorates diabetes induced cognitive dysfunction and improves BDNF expression

  

PPARγ Recruitment to Active ERK during Memory Consolidation Is Required for Alzheimer's Disease-Related Cognitive Enhancement

Cognitive impairment is a quintessential feature of Alzheimer's disease (AD) and AD mouse models. The peroxisome proliferator-activated receptor-γ (PPARγ) agonist rosiglitazone improves hippocampus-dependent cognitive deficits in some AD patients and ameliorates deficits in the Tg2576 mouse model for AD amyloidosis. Tg2576 cognitive enhancement occurs through the induction of a gene and protein expression profile reflecting convergence of the PPARγ signaling axis and the extracellular signal-regulated protein kinase (ERK) cascade, a critical mediator of memory consolidation. We therefore tested whether PPARγ and ERK associated in protein complexes that subserve cognitive enhancement through PPARγ agonism. Coimmunoprecipitation of hippocampal extracts revealed that PPARγ and activated, phosphorylated ERK (pERK) associated in Tg2576 in vivo, and that PPARγ agonism facilitated recruitment of PPARγ to pERK during memory consolidation. Furthermore, the amount of PPARγ recruited to pERK correlated with the cognitive reserve in humans with AD and in Tg2576. Our findings implicate a previously unidentified PPARγ–pERK complex that provides a molecular mechanism for the convergence of these pathways during cognitive enhancement, thereby offering new targets for therapeutic development in AD.

Cognitive Enhancementwith Rosiglitazone Links the Hippocampal PPAR gamma and ERK MAPK Signaling Pathways

Pathogenesis of Alzheimer’s and Diabetes

The pathogenesis of a disease is the biological mechanism (or mechanisms) that lead to the diseased state.

I am not suggesting that autism leads to Alzheimer’s.  (We do though know that most people with Down Syndrome will develop early Alzheimer’s in their 40s or 50s)

Many complex diseases like Alzheimer’s, cancer and indeed autism have multiple biological mechanisms behind them.

By studying the molecular pathways involved in one disease it may help understand another disease.  This is why some readers of this blog follow the cancer/oncology research.

For some time I have been intrigued at the overlap between diabetes and autism.  What is good for autism really does seem to be good for diabetes and vice versa.

Alzheimer’s Disease as Type 3 Diabetes

I was surprised to learn that some clinicians now consider Alzheimer’s Disease as Type 3 Diabetes.           

You will recall that Type 1 diabetes is when your pancreas packs up making insulin and then you have to inject yourself with supplementary insulin.

Type 2 diabetes occurs in late middle age, often linked to obesity, and is characterized by high blood sugar, insulin resistance (insulin sensitivity), and relative lack of insulin.

Insulin resistance (IR) is generally regarded as a pathological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin. When the body produces insulin under conditions of insulin resistance, the cells in the body are resistant to the insulin and are unable to use it as effectively, leading to high blood sugar. Beta cells in the pancreas subsequently increase their production of insulin, further contributing to a high blood insulin level. This often remains undetected and can contribute to a diagnosis of Type 2 diabetes.  Despite the ill-effects of severe insulin resistance, recent investigations have revealed that insulin resistance is primarily a well-evolved mechanism to conserve the brain's glucose consumption by preventing muscles from taking up excessive glucose.^[

Eventually Type 2 diabetes may progress to Type 1 diabetes mellitus, where the body's own immune system attacks the beta cells in the pancreas and destroys them. This means the body can no longer produce and secrete insulin into the blood and regulate the blood glucose concentration. We saw how the use of Verapamil can stop beta cells being destroyed.

Some clinicians/researchers propose that diabetes of the brain should be called Type 3 diabetes.

The research does support the view that Alzheimer’s does incorporate this brain-specific type of diabetes.  But I know wonder if this applies to some autism.

Alzheimer’s Disease Is Type 3 Diabetes—Evidence Reviewed

Alzheimer’s disease (AD) has characteristic histopathological, molecular, and biochemical abnormalities, including cell loss; abundant neurofibrillary tangles; dystrophic neurites; amyloid precursor protein, amyloid-β (APP-Aβ) deposits; increased activation of prodeath genes and signaling pathways; impaired energy metabolism; mitochondrial dysfunction; chronic oxidative stress; and DNA damage. Gaining a better understanding of AD pathogenesis will require a framework that mechanistically interlinks all these phenomena. Currently, there is a rapid growth in the literature pointing toward insulin deficiency and insulin resistance as mediators of AD-type neurodegeneration, but this surge of new information is riddled with conflicting and unresolved concepts regarding the potential contributions of type 2 diabetes mellitus (T2DM), metabolic syndrome, and obesity to AD pathogenesis. Herein, we review the evidence that (1) T2DM causes brain insulin resistance, oxidative stress, and cognitive impairment, but its aggregate effects fall far short of mimicking AD; (2) extensive disturbances in brain insulin and insulin-like growth factor (IGF) signaling mechanisms represent early and progressive abnormalities and could account for the majority of molecular, biochemical, and histopathological lesions in AD; (3) experimental brain diabetes produced by intracerebral administration of streptozotocin shares many features with AD, including cognitive impairment and disturbances in acetylcholine homeostasis; and (4) experimental brain diabetes is treatable with insulin sensitizer agents, i.e., drugs currently used to treat T2DM. We conclude that the term “type 3 diabetes” accurately reflects the fact that AD represents a form of diabetes that selectively involves the brain and has molecular and biochemical features that overlap with both type 1 diabetes mellitus and T2DM.

Altogether, the results from these studies provide strong evidence in support of the hypothesis that AD represents a form of diabetes mellitus that selectively afflicts the brain

The human and experimental animal model studies also showed that CNS impairments in insulin/IGF signaling mechanisms can occur in the absence of T1DM or T2DM

Altogether, the data provide strong evidence that AD is intrinsically a neuroendocrine disease caused by selective impairments in insulin and IGF signaling mechanisms, including deficiencies in local insulin and IGF production.

At the same time, it is essential to recognize that T2DM and T3DM are not solely the end results of insulin/IGF resistance and/or deficiency, because these syndromes are unequivocally accompanied by significant activation of inflammatory mediators, oxidative stress, DNA damage, and mitochondrial dysfunction, which contribute to the degenerative cascade by exacerbating insulin/ IGF resistance.

Some of the most relevant data supporting this concept have emerged from clinical studies demonstrating cognitive improvement and/or stabilization of cognitive impairment in subjects with early AD following treatment with intranasal insulin or  a PPAR agonist

Repurposing Diabetes Drugs for Brain Insulin Resistance in Alzheimer Disease

 Although many classes of drugs are now approved for management of diabetes, a primary focus of efforts to treat insulin-signaling dysfunction in AD has been the administration of exogenous insulin. There is abundant anecdotal evidence that insulin administration in people with diabetes may acutely affect mood, behavior, and cognitive performance.

Results of recent pilot studies of intranasal insulin in mild cognitive impairment (MCI) and AD have been encouraging. The most notable of these studies was a doubleblind, randomized trial of 104 older adults with MCI or AD who received placebo, low-dose (20 IU), or high-dose (40 IU) intranasal insulin for 4 months

In 2012, the U.S. National Institutes of Health allocated $7.9 million for a pivotal trial of intranasal insulin called the Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF; ClinicalTrials identifier: NCT01767909). This multicenter phase 2/3 study will be conducted by the ADCS. It is expected to recruit 250 participants with AD or MCI and to randomize them for 12 months to intranasal insulin or placebo, followed by an open-label extension of 6 months in which all participants will receive intranasal insulin. The study should be completed in late 2014.  The Study of Nasal Insulin in the Fight Against Forgetfulness (SNIFF)

In preclinical studies, TZDs improved biomarkers of AD as well as memory and cognition (31). The first pilot studies in humans were also generally encouraging, including a study by Watson et al. (32) that showed improved memory and modulation of amyloid-b levels in CSF compared with placebo after 6 months of treatment with rosiglitazone. On the basis of these preliminary studies, the maker of rosiglitazone sponsored two adequately powered phase 3 studies of rosiglitazone in AD as monotherapy or as adjunctive therapy to acetylcholinesterase inhibitors in mild to-moderate AD. These larger trials failed to replicate the positive findings of the smaller pilot studies (33).

Many explanations have been proposed for why rosiglitazone does not appear to be effective as a treatment for AD in cognitively impaired adults. Perhaps the most convincing explanation is that rosiglitazone has only modest blood-brain barrier penetration, and in fact, rosiglitazone is actively pumped out of the brain by an endogenous efflux system (34). Therefore, rosiglitazone should be expected to have only a mild insulin-sensitizing effect in the human brain.

   

Conclusion

The type 2 diabetes drugs like Rosiglitazone/Pioglitazone have been trialed in both autism and Alzheimer’s.  The results in autism with pioglitazone were positive, in Alzheimer’s they used Rosiglitazone, due to the adverse side effects of pioglitazone, and the results were very mixed.  Rosiglitazone has only modest blood-brain barrier penetration so it looks a poor choice.

In the autism trial they measured "autism" rather than cognitive function.

Effect of pioglitazone treatment on behavioral symptoms in autistic children 

In a small cohort of autistic children, daily treatment with 30 or 60 mg p.o. pioglitazone for 3–4 months induced apparent clinical improvement without adverse events. There were no adverse effects noted and behavioral measurements revealed a significant decrease in 4 out of 5 subcategories (irritability, lethargy, stereotypy, and hyperactivity). Improved behaviors were inversely correlated with patient age, indicating stronger effects on the younger patients.

Conclusion  Pioglitazone should be considered for further testing of therapeutic potential in autistic patients.

One to watch is the effect of the standard type 2 diabetes treatment Metformin on cognition in Alzheimer’s.  Nobody really knows the mode of action of Metformin.

Effect of Insulin Sensitizer Metformin on AD Biomarkers

Repurposing metformin: an old drug with new tricks in its binding pockets

Intranasal insulin is very interesting and not just in Alzheimer’s.

Intranasal insulin improves memory in humans

Intranasal Insulin as a Treatment for Alzheimer’s Disease: A Review of Basic Research and Clinical Evidence

Intranasal Insulin Improves Age-Related Cognitive Deficits and Reverses Electrophysiological Correlates of Brain Aging

I will add it to my growing list of therapies for mild cognitive impairment, in case I need it in the future.

·        Nerve growth factor (NGF) eye drops
·        Lions Mane Mushrooms (that increase NGF)
·        Cocoa Flavanols (increase cerebral blood flow)
·        Intranasal insulin or just Tangeritin/Sytrinol

I do not know if intranasal insulin would be a safe long-term therapy for children, but it would be a good diagnostic tool.  Once large numbers of older people start using intranasal insulin for cognition, we will find out how well it is tolerated.  Older people seem far more prone to side effects than younger people.


For now I think Tangeritin/Sytrinol is the best choice.

Yale, Autism and Morphology

  

In a recent post I introduced a new term – morphology.  Some scientific jargon serves to make things more confusing for the lay reader, but this really is a useful term to understand autism.

Morphology, in biology, the study of the size, shape, and structure of animals, plants, and microorganisms and of the relationships of the parts comprising them.

Today we are talking about morphology as it relates to the growth of the human body in autism.

In earlier posts relating to hormones and growth factors (endocrinology) I made my own observations about Monty, aged 11 with ASD.  I commented how he fell from the 80% percentile in height, aged 2, to the 20^th percentile, where he is now.  I also noted how he went from very muscular to your average “floppy” toddler.

I did discuss this with a pediatric endocrinologist and asked what is the point of collecting this height and weight data for children, if nothing is done with it.  I did tell her all about the emerging use of the growth factor IGF-1 in treating autism and also the hypothesis that people with autism have low thyroid hormone T3 in the brain.

I concluded that endocrinologists do not know anything about autism, but I did learn all about bone age. 

Endocrinologists often use X rays of the hand to look for advanced or delayed bone age.  They look at the gaps in between the small bones to assess the degree of maturation.  The bigger the gap, the less mature the bones.  They have a big book of X-rays and they just flip through the pages until they find one like your X ray.  So if you are 11 years old, with bone structure of a 9 year old, then you would have delayed bone age.  In practical terms, this means you are likely to keep growing for longer than the average child.

Autism Research

As we have seen already, much data in autism is of dubious quality.  Studies are contradictory.  Much of this is due to mixing apples with kiwis and even pineapples. You cannot usefully compare data on severely autistic people with those ever so mildly affected, but still “autistic” by DSM. Even separating early onset and regressive autism is rare in studies.  There is no agreement as to what regressive really means and some scientists even think regression is just a development plateau – I guess they never see actual patients.

So I was pleased to come across some interesting research about autism morphology that seems credible.  Of all places, it was in a student publication from Yale.  On Facebook, Monty’s older brother keeps getting confused with his namesake, who is one of the reporters on the Yale student newspaper.    Not only does Yale have a daily student newspaper, but it also has its own Yale Scientific Magazine.

They must have a lot of free time over at Yale.

This was my first experience of student journalism at Yale.  I was impressed.

Autism may be predicted by overgrowth

Sizing Up Autism: The CorrelationBetween Autism and Abnormal Growth

  

One identified phenotype associated with autism is abnormally large Total Cerebral Volume (TCV) and, correspondingly, Head Circumference (HC) – collectively called macrocephaly. Researchers at Yale University’s Child Study Center have undertaken studies in the connectivity of growth and neural development to assess risk and predict developmental phenotype of young boys through growth measurement. A group of 184 boys aged birth to 24 months, composed of 55 typically developing controls, 64 with ASD, 34 with Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS), 13 with global developmental delays, and 18 with other developmental problems, was analyzed for head circumference, height, weight, and social, verbal and cognitive functioning. Boys with autism were significantly taller by 4.8 months, had a larger HC by 9.5 months, weighed more by 11.4 months, were in the top ten percent in size in infancy (correlated with lower adaptive functioning and social deficits), and showed accelerated HC growth in the first year of life.  


Here is actual study:-

Early Generalized Overgrowth in Boys With Autism

Main Outcome Measures: Age-related changes in HC (head circumference),

height, and weight between birth and age 24 months; measures of social, verbal, and cognitive functioning at age 2 years.

Results: Compared with typically developing controls, boys with autism were significantly longer by age 4.8 months, had a larger HC by age 9.5 months, and weighed more by age 11.4 months (P=.05 for all). None of the other clinical groups showed a similar overgrowth pattern. Boys with autism who were in the top 10% of overall physical size in infancy exhibited greater severity of social deficits (P=.009) and lower adaptive functioning (P=.03).

Conclusions: Boys with autism experienced accelerated HC growth in the first year of life. However, this phenomenon reflected a generalized process affecting other morphologic features, including height and weight. The

study highlights the importance of studying factors that influence not only neuronal development but also skeletal growth in autism.

  

The Yale researcher is Polish, as was the lady who wrote about oxidative stress in the brain lowering D2 and hence thyroid hormone T3 in the brain.

Conclusion

This does take us back to the earlier posts on human growth factors.  It does seem that at least in one sub-type of autism there is “excess” growth in the first two years that is visible in terms of morphology.  This growth spurt then halts.

We already have data showing that in autism the brain itself also “over-grows” up to the age of about three.  We can now generalize that in this sub-type everything is likely affected by this over-growth.

Why does the growth spurt halt? It is not for lack of the growth factor IGF-1, many people with autism actually have elevated levels of this growth factor.  It is simple and inexpensive to check; I did it.

The problem may relate to something called Akt, also known as protein kinase B (PKB).

IGF-1 is one of the most potent natural activators of the AKT signaling pathway, a stimulator of cell growth and proliferation.

Very recent research has highlighted abnormalities in the IGF-1 – Akt pathway and also in similar pathways related to the brain’s own growth factor, BDNF.  (Note that mTOR is also implicated in autism)

Dysregulation of the IGF-I/PI3K/AKT/mTOR signaling pathway in autism spectrum disorders

 Abnormalities in BDNF/TrkB/PI3Ksignaling pathways in autism

So while IGF-1 may be an effective therapy for some people with autism (it is already used experimentally), most likely the real problem is slightly different and a better intervention might relate to AKT/PKB.

We will follow up on these and other protein kinase shortly.

IL-6 Disrupts the GH→IGF-1 Axis in Autism

 

Regular readers of this blog will see that there is an underlying logic behind recent posts.  We know levels of the cytokine IL-6 are raised in autism and we know that high levels of IL-6 in mice produces a baby with autism and we know this can be reversed by giving IL-6 antibodies to the mother, prior to birth.
We also know from numerous previous posts that growth hormone (GH) and the growth factor IGF-1 are implicated in autism.  Both GH and IGF-1 are used in clinical trials for autism.

Today’s post draws all this together.  It turns out that IL-6 disrupts the GH-IGF-1 axis.  The hormone GH is supposed to control the release of IGF-1; so a little more GH should produce a little more IGF-1.  The problem is that the cytokine IL-6 disrupts this relationship.  In the presence of elevated amounts of IL-6, which is characteristic of autism, and regressive autism in particular, GH does not produce the expected increase in IGF-1; IGF-1 levels are actually reduced.

This is very important.

A great deal of money is being spent researching and developing IGF-1 based therapies for autism and Retts syndrome.  Perhaps a much better strategy would be to clear the disruption from the GH-IGF-1 axis, so that IGF-1 levels could be restored naturally.  This means reducing IL-6 levels and IL-6 mediated disruption. We already know how to do this, from previous posts.

Now for some supporting evidence:-

In the following study, IL-6 was given to healthy volunteers and the over the next 8 hours their levels of GH and IGF-1 were measured.

The study confirmed earlier observations that IL-6 infusion leads to increased circulating GH. Despite the increase in GH levels, the study demonstrated an IL-6 infusion-associated reduction in IGF-I. 

Effect of rhIL-6 infusion on GH→IGF-I axis mediators in humans

 

Coming back to mice being given IL-6 to produce autistic pups, Autism Speaks funded a very thorough post-doctoral study at Caltech that focused on understanding this very issue (in mice at least).  The study aimed to find out how IL-6 ends up causing autism.  The conclusion is very interesting and again comes back to endocrine changes and the disrupted GH-IGF-1 axis.

I rest my case. 

Activation of the maternal immune system induces endocrine changes in the placenta via IL-6

"Activation of the maternal immune system in rodent models sets in motion a cascade of molecular pathways that ultimately result in autism- and schizophrenia-related behaviors in offspring. The finding that interleukin-6 (IL-6) is a crucial mediator of these effects led us to examine the mechanism by which this cytokine influences fetal development in vivo. Here we focus on the placenta as the site of direct interaction between mother and fetus and as a principal modulator of fetal development. We find that maternal immune activation (MIA) with a viral mimic, synthetic double-stranded RNA (poly(I:C)), increases IL-6 mRNA as well as maternally-derived IL-6 protein in the placenta. Placentas from MIA mothers exhibit increases in CD69+ decidual macrophages, granulocytes and uterine NK cells, indicating elevated early immune activation. Maternally-derived IL-6 mediates activation of the JAK/STAT3 pathway specifically in the  pongiotrophoblast layer of the placenta, which results in expression of acute phase genes. Importantly, this parallels an IL-6-dependent disruption of the growth hormone-insulin-like growth factor (GHIGF) axis that is characterized by decreased GH, IGFI and IGFBP3 levels. In addition, we observe an IL-6-dependent induction in pro-lactin-like protein-K (PLP-K) expression as well as MIA-related alterations in other placental endocrine factors. Together, these IL-6-mediated effects of MIA on the placenta represent an indirect mechanism by which MIA can alter fetal development. 

Furthermore, we find an IL-6-dependent dysregulation of the GH-IGF axis in MIA placentas, characterized by decreased levels of GH and IGFI mRNA, with corresponding decreases in placental IGFI and IGFBP3 protein. The actions of GH are achieved through the stimulation of IGFI production in target tissues. In addition, GH regulates the activity of IGFI by altering the production of either facilitatory or inhibitory binding proteins, including the IGFI stabilizing protein, IGFBP3. This suggests that the decreased GH levels seen in MIA placentas leads to the observed downstream suppression of IGFBP3 and IGFI production. It is believed that IGFs in the maternal circulation do not enter the placenta, and therefore IGFs in the placenta are derived from the placental compartment itself We demonstrate that the changes in IGFI and IGFBP3 expression are mediated by IL-6. However, it is unclear whether decreases in placental GH and subsequent effects on IGF production are downstream of IL-6-specific STAT3 activation. IL-6 does modulate IGFI and IGFBPs in several tissues, including placenta and cord blood. Pro-inflammatory cytokines, including IL-6, decrease circulating and tissue concentrations of GH and IGFI. We observe that IL-6- mediated STAT3 activation is associated with the expected IL-6- mediated increase in SOCS3 expression, along with other acute phase genes. Factors like SOCS play an important role in the down-regulation of GH and GH signaling. Importantly, it is reported that IL-6 inhibits hepatic GH signaling through up-regulation of SOCS3. As such, it is possible that, in MIA placentas, maternal IL-6-induced STAT3 activation and downstream sequelae lead to suppression of placental GH levels, disruption of IGFI production and further consequences on maternal physiology, placental function and fetal development. Altered placental physiology and release of deleterious mediators to the fetus are important risk factors for the pathogenesis of neurodevelopmental disorders. Placental IGFI in particular regulates trophoblast function , nutrient partitioning and placental efficiency. Moreover, altered IGFI levels are associated with intrauterine growth restriction (IUGR) and abnormal development. Animal models of IUGR and intrauterine infection, where the immune insult is confined to the uteroplacental compartment, highlight the key role of placental inflammation in perinatal brain damage, involving altered cortical astrocyte development, white-matter damage, microglial activation, cell death and reduced effectiveness of the fetal blood–brain barrier. In addition, adult pathophysiology is subject to feto-placental ‘‘programming’’, wherein molecular changes that occur prenatally reflect permanent changes that persist throughout postnatal life. Interestingly, placental responses to maternal insults can potentiate sexually dimorphic effects on fetal development. Obstetric complications are linked to schizophrenia risk and to the treatment responses of schizophrenic individuals. Notably, a greater occurrence of placental trophoblast inclusions was observed in placental tissue from children who develop autism spectrum disorder (ASD) compared to non-ASD controls. Chorioamnionitis and other obstetric complications are significantly associated with socialization and communication deficitis in autistic infants. The characterization of placental pathophysiology and obstetric outcome in ASD and schizophrenic individuals will be useful for the identification of molecular mechanisms that underlie these disorders and for potential biomarkers for early risk diagnosis. In addition to the observed effects of IL-6 on placental physiology and its downstream effects on fetal brain development and postnatal growth, direct effects of IL-6 on the fetal brain are also likely. Maternal IL-6 can potentially cross the placenta and enter the fetus after MIA. Furthermore, IL-6 mRNA and protein are elevated and STAT3 is phosphorylated in the fetal brain itself following MIA, raising the obvious possibility that IL-6 acts directly on the developing brain to influence astrogliosis, neurogenesis, microglial activation and/or synaptic pruning. However, recall that the identification of IL-6 as a critical mediator of MIA is based on maternal co-injection of poly(I:C) and anti-IL-6 blocking antibody, in addition to experiments inducing MIA in IL-6 KO animals. As such, in considering which pool(s) of IL-6 (e.g. maternal, placental, fetal brain, fetal periphery) is the ‘‘critical mediator’’, it will be important to understand the potential interaction between maternal IL-6 and fetal brain IL-6 expression. While we believe that the endocrine changes triggered by maternal-IL-6 signaling in the placenta reported here are important for fetal growth, it will be crucial to assess the potential impact of these placental changes on offspring behavior and neuropathology. We are currently exploring the effects of MIA in targeted IL-6Ra KOs in order to tie tissue- and cell-specific IL-6 activity to the manifestation of schizophrenia- and autism-related endophenotypes."