I am gradually tying up the loose ends in this blog. Today several issues are dealt with that are all connected by zinc. Some are extremely complicated and I will skip over the details.
Not that kind of hedgehog
1. In those rather complicated graphics in the literature that explain signaling pathways, you may have noticed something called hedgehog signaling. This is a basic pathway present in all bilaterians - creatures with a head and tail/feet and a left and right. So flies, yes; but jelly fish, no. In autism there is excessive hedgehog signaling. Zinc deficiency is linked to activation of the hedgehog signaling pathway
2. One of the commonly used models of autism is called Shank3; there is another one called Shank2. Shank proteins are scaffold proteins that connect neurotransmitter receptors and ion channels to the actin cytoskeleton and G-protein-coupled signaling pathways. Mutations in these genes are associated with autism. This gets very complicated.
3. In trying to consider all types of excitatory–imbalance in autism we have yet to look into how low levels of zinc inactivate Shank2 (and so inactivate NMDA receptors) and also inactivate Shank3 reducing synaptic transmission via AMPA receptors as well.
4. In earlier posts there have been references to zinc in autism and it was suggested that the Zn2+ ions are in the “wrong place”.
5. In people with autism very often there appears to be high levels of copper, but low levels of zinc.
6. There is a paradoxical relationship where high levels of zinc supplementation actually causes zinc deficiency in the hippocampus
While you might not read much about zinc and autism, it clearly is very relevant but only partially understood.
Much of the early research regarding zinc and autism has been very simplistic and tells you little. Recently research has been far from trivial and is getting into the details; look for terms such as Shank2, Shank3, and even Shankopathies.
If someone with autism is deficient in zinc, supplementation may indeed have a positive effect, but high doses of oral zinc will actually cause deficiency in the brain.
In the brain, zinc is stored in specific synaptic vesicles by glutamatergic neurons and can modulate neuronal excitability. It plays a key role in synaptic plasticity and so in learning.
Zinc can also be a neurotoxin, suggesting zinc homeostasis plays a critical role in the functional regulation of the central nervous system. Dysregulation of zinc homeostasis in the central nervous system that results in excessive synaptic zinc concentrations is believed to induce neurotoxicity through mitochondrial oxidative stress, the dysregulation of calcium homeostasis, glutamate excitotoxicity, and interference with intra-neuronal signal transduction.
Zinc is the authoritative metal which is present in our body, and reactive zinc metal is crucial for neuronal signaling and is largely distributed within presynaptic vesicles. Zinc also plays an important role in synaptic function. At cellular level, zinc is a modulator of synaptic activity and neuronal plasticity in both development and adulthood. Different importers and transporters are involved in zinc homeostasis. ZnT-3 is a main transporter involved in zinc homeostasis in the brain. It has been found that alterations in brain zinc status have been implicated in a wide range of neurological disorders including impaired brain development and many neurodegenerative disorders such as Alzheimer's disease, and mood disorders including depression, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and prion disease. Furthermore, zinc has also been implicated in neuronal damage associated with traumatic brain injury, stroke, and seizure. Understanding the mechanisms that control brain zinc homeostasis is thus critical to the development of preventive and treatment strategies for these and other neurological disorders.
For a full list of zinc transporters and disease associations click the link below
Most likely the problem in autism is caused by zinc transporters. In schizophrenia it is suggested that the zinc transporter ZIP12/ SLC39A12 is over-expressed.
Increased cortical expression of the zinc transporter SLC39A12 suggests a breakdown in zinc cellular homeostasis as part of the pathophysiology of schizophrenia
You may wonder what could be the connection between zinc, hedgehogs and autism, but today I am talking about a special kind of hedgehog, the evolutionarily conserved Hedgehog (Hh) pathway; there really is a connection.
Sonic hedgehog is a protein that in humans is encoded by the SHH (sonic hedgehog) gene. Sonic hedgehog is one of three proteins in the mammalian signaling pathway family called hedgehog, the others being Desert hedgehog (DHH) and Indian hedgehog (IHH). SHH is the best studied of the hedgehog signaling pathway.
Both sonic and Indian hedgehog are consistently found elevated in autism. Desert hedgehog gets much less attention, but was found to be reduced in one study from Saudi Arabia, no surprise they choose the desert variant.
Sonic hedgehog is seen as the most important in development and is heavily implicated in some cancers. It plays a role in how your teeth grow, how your lungs grow, how your hair regenerates and very many other things.
The next graphic is complicated and most people will skip it.
The evolutionarily conserved Hedgehog (Hh) pathway is essential for normal embryonic development and plays critical roles in adult tissue maintenance, renewal and regeneration. Secreted Hh proteins act in a concentration- and time-dependent manner to initiate a series of cellular responses that range from survival and proliferation to cell fate specification and differentiation.
Proper levels of Hh signaling require the regulated production, processing, secretion and trafficking of Hh ligands– in mammals this includes Sonic (Shh), Indian (Ihh) and Desert (Dhh). All Hh ligands are synthesized as precursor proteins that undergo autocatalytic cleavage and concomitant cholesterol modification at the carboxy terminus and palmitoylation at the amino terminus, resulting in a secreted, dually-lipidated protein. Hh ligands are released from the cell surface through the combined actions of Dispatched and Scube2, and subsequently trafficked over multiple cells through interactions with the cell surface proteins LRP2 and the Glypican family of heparan sulfate proteoglycans (GPC1-6).
Hh proteins initiate signaling through binding to the canonical receptor Patched (PTCH1) and to the co-receptors GAS1, CDON and BOC. Hh binding to PTCH1 results in derepression of the GPCR-like protein Smoothened (SMO) that results in SMO accumulation in cilia and phosphorylation of its cytoplasmic tail. SMO mediates downstream signal transduction that includes dissociation of GLI proteins (the transcriptional effectors of the Hh pathway) from kinesin-family protein, Kif7, and the key intracellular Hh pathway regulator SUFU.
GLI proteins also traffic through cilia and in the absence of Hh signaling are sequestered by SUFU and Kif7, allowing for GLI phosphorylation by PKA, GSK3β and CK1, and subsequent processing into transcriptional repressors (through cleavage of the carboxy-terminus) or targeting for degradation (mediated by the E3 ubiquitin ligase β-TrCP). In response to activation of Hh signaling, GLI proteins are differentially phopshorylated and processed into transcriptional activators that induce expression of Hh target genes, many of which are components of the pathway (e.g. PTCH1 and GLI1). Feedback mechanisms include the induction of Hh pathway antagonists (PTCH1, PTCH2 and Hhip1) that interfere with Hh ligand function, and GLI protein degradation mediated by the E3 ubiquitin ligase adaptor protein, SPOP.
In addition to vital roles during normal embryonic development and adult tissue homeostasis, aberrant Hh signaling is responsible for the initiation of a growing number of cancers including, classically, basal cell carcinoma, edulloblastoma, and rhabdomyosarcoma; more recently overactive Hh signaling has been implicated in pancreatic, lung, prostate, ovarian, and breast cancer. Thus, understanding the mechanisms that control Hh pathway activity will inform the development of novel therapeutics to treat a growing number of Hh-driven pathologies.
Sonic Hedgehog Protein correlates with severity of autism
The research does show that the more severe the autism, the higher is the level of sonic hedgehog protein.
Relationship Between Sonic Hedgehog Protein, Brain-Derived Neurotrophic Factor and Oxidative Stress in Autism Spectrum Disorders
Serum levels of Sonic hedgehog protein in control and autistic children.
Highly statistically significant Sonic hedgehog serum level in mild and severe autism
Zinc deficiency activates hedgehog signaling
Background: In many types of cancers zinc deficiency and overproduction of Hedgehog (Hh) ligand co-exist.
Results: Zinc binds to the active site of the Hedgehog-intein (Hint) domain and inhibits Hh ligand production both in vitro and in cell culture.
Conclusion: Zinc influences the Hh autoprocessing.
Results: Zinc binds to the active site of the Hedgehog-intein (Hint) domain and inhibits Hh ligand production both in vitro and in cell culture.
Conclusion: Zinc influences the Hh autoprocessing.
Significance: This study uncovers a novel mechanistic link between zinc and the Hh signaling pathway.
DISCUSSIONZinc is an essential trace element, acting as a co-factor for >300 enzymes that regulate a variety of cellular processes and signaling pathways (38). Zinc is also a signaling molecule and can modulate synaptic activity (39). The imbalance of zinc homeostasis has been established in many pathological conditions (14–21), including many types of cancer and autism. However, the mechanistic role of zinc deficiency in these diseases remains poorly understood.
ASD, with an astounding prevalence of ∼2% (43), is characterized by abnormal social interaction, communication, and stereotyped behaviors in affected children. The etiology of ASD is poorly understood, but both oxidative stress (44) and low zinc status have been reproducibly associated with ASD (16, 45). In astrocyte culture, Hh autoprocessing is promoted by H2O2 and low zinc level (Fig. 2A), offering a plausible mechanistic explanation for the recent observation of increased serum level of sonic Hh ligand in ASD (9). The resulting higher level of secreted Hh ligand may lead to the abnormal activation of Hh signaling pathway in both neurons and glial cells in the developing brain. A clinical feature of ASD, macrocephaly, also implicates Hh activation (46–48). Hh plays an important role in the early expansion of the developing brain and in regulating the cerebral cortical size (49, 50). In contrast, the opposite clinical feature, microcephaly, is observed in holoprosencephaly (51), which can be caused by mutations in the Hh autoprocessing domain (HhC) that reduce Hh ligand production (51–54). The abnormal activation of Hh pathway, even transiently by fluctuations in zinc level, may cause brain overgrowth, disrupting the proper development of neuronal network for language and social interactions. We, therefore, hypothesize that in ASD low zinc status promotes Hh autoprocessing and the generation of higher level of Hh ligand. Coupled with oxidative and/or genetic defects in other Hh signaling components, low zinc status may lead to abnormal activation of Hh signaling pathway during brain development, contributing to the complex etiology of ASD.
The etiology of autism spectrum disorders (ASD) is not well known but recently we reported that the serum levels of sonic hedgehog (SHH) protein and brain-derived neurotrophic factor (BDNF) might be linked to oxidative stress in ASD. We hypothesized that Indian hedgehog (IHH) protein which belongs to SHH family may play a pathological role in the ASD. We studied recently diagnosed patients in early stages of ASD (n=54) and age-matched, cognitively normal, individuals (n=25), using serum levels of IHH protein. We found statistically significantly higher-levels of serum IHH protein in ASD subjects (p=0.001) compared to control subjects. Our findings are the first to report a role of IHH in ASD children, suggesting a possible pathological role-played by IHH in early-stage in ASD. Such measures might constitute an early biomarker for ASD and ultimately offer a target for novel biomarker-based therapeutic interventions.
Too much zinc causes Hippocampal Zinc Deficiency
Before you rush to buy some zinc tablets, you should read the next study.
High Dose Zinc Supplementation Induces Hippocampal Zinc Deficiency and Memory Impairment with Inhibition of BDNF Signaling
These results indicate that zinc plays an important role in hippocampus-dependent learning and memory and BDNF expression, high dose supplementation of zinc induces specific zinc deficiency in hippocampus, which further impair learning and memory due to decreased availability of synaptic zinc and BDNF deficit.
Consistent with previous reports, zinc supplementation in low dosage may increase the anxiety level , .The previous data regarding the low dose zinc supplementation on learning and memory was conflicting. Flinn JM et al. reported in a series of publications that enhanced zinc (10 ppm) consumption causes memory deficits in rats ,  and potentiates memory impairment in transgenic disease mouse models , , while others observed improved performance of the animals in spatial memory tasks , . In our experiments, we also observed improved performance of mice in contextual discrimination task. The underlying mechanism for the memory improvement by low dose zinc supplement needs further exploration. On the contrary, zinc supplementation in high dose resulted in impaired spatial memory. Interestingly, the memory deficit seemed to be highly hippocampus dependent, since high dose supplementation of zinc only impaired the performance of the mice in context discrimination but not in contextual conditioning
The possible positive effect of zinc supplementation in Autism
There was a Phase 1 clinical trial at Penn State (by Jeanette C. Ramer) looking at the level of copper and zinc in autism and then supplementing vitamin C and zinc. The study was completed a few years ago but it looks like they never published the results. We have to assume it was inconclusive, but it would nice if they published the results anyway.
The study below was funded by the Autism Research Institute.
Analysis of Copper and Zinc Plasma Concentration and the Efficacy of Zinc Therapy in Individuals with Asperger’s Syndrome, Pervasive Developmental Disorder Not Otherwise Specified (PDD-NOS)and Autism
To assess plasma zinc and copper concentration in individuals with Asperger’s Syndrome, Pervasive Developmental Disorder-Not Otherwise Specified (PDD-NOS) and autistic disorder, and to analyze the efficacy of zinc therapy on the normalization of zinc and copper levels and symptom severity in these disorders.
Subjects and methods
Plasma from 79 autistic individuals, 52 individuals with PDD-NOS, 21 individuals with Asperger’s Syndrome (all meeting DSM-IV diagnostic criteria), and 18 age and gender similar neurotypical controls, were tested for plasma zinc and copper using inductively-coupled plasma-mass spectrometry.
Autistic and PDD-NOS individuals had significantly elevated plasma levels of copper. None of the groups (autism, Asperger’s or PDD-NOS) had significantly lower plasma zinc concentrations. Post zinc and B-6 therapy, individuals with autism and PDD-NOS had significantly lower levels of copper, but individuals with Asperger’s did not have significantly lower copper. Individuals with autism, PDD-NOS and Asperger’s all had significantly higher zinc levels. Severity of symptoms decreased in autistic individuals following zinc and B-6 therapy with respect to awareness, receptive language, focus and attention, hyperactivity, tip toeing, eye contact, sound sensitivity, tactile sensitivity and seizures. None of the measured symptoms worsened after therapy. None of the symptoms in the Asperger’s patients improved after therapy.
These results suggest an association between copper and zinc plasma levels and individuals with autism, PDD-NOS and Asperger’s Syndrome. The data also indicates that copper levels normalize (decrease to levels of controls) in individuals with autism and PDD-NOS, but not in individuals with Asperger’s. These same Asperger’s patients do not improve with respect to symptoms after therapy, whereas many symptoms improved in the autism group. This may indicate an association between copper levels and symptom severity.
Our study shows that autistic individuals have lower levels of zinc and significantly higher levels of copper when compared to neurotypical controls.
We do not know why copper doesn’t normalize after zinc therapy in Asperger’s patients but suggest that since symptom severity of these patients remains high, high copper levels are most likely associated with symptom severity.
Individuals in this study who presented to the Pfeiffer Treatment Center with depression (or anxiety) were tested for Zn, Cu and anti-oxidant levels. Based on deficiencies, they were then prescribed the appropriate dose of anti-oxidants. Pre-therapy patients represent those who were tested when they first presented and were not previously taking any Zn or anti-oxidants. Post-Therapy patients received anti-oxidant therapy (Vitamin C, E, B-6 as well as Magnesium, and Manganese if warranted), and Zn supplementation (as Zn picolinate), daily, for a minimum of 8 weeks.
Trans-synaptic zinc mobilization
I did write a post a while back about some very interesting findings from Taiwan.
In their research they found that simply repositioning zinc improved social interaction in two models of autism and they proposed a trial in humans with a drug already licensed in Taiwan. They also had to suggestions for people with autism.
Hsueh recommends that people with autism who are diagnosed with zinc deficiency caused by the underexpression of the NMDAR receptor to increase their zinc intake by eating food high in zinc, such as oysters. She added that meat, which is rich in protein, helps boost zinc absorption.
Trans-synaptic zinc mobilization improves social interaction in two mouse models of autism through NMDAR activationgh NMDAR activation
In the present study, we demonstrate that trans-synaptic Zn mobilization by clioquinol, a Zn chelator and ionophore (termed CQ hereafter), rescues the social interaction deficits in Shank2_/_ and Tbr1þ/_ mice. CQ mobilizes Zn from enriched presynaptic pools to postsynaptic sites, where it enhances NMDAR function through Src activation. These results indicate that postsynaptic Zn rescues social interaction deficits in distinct mouse models of ASDs, and suggest that reduced NMDAR function is associated with ASDs.
In the present study, we found that trans-synaptic Zn mobilization improves social interaction in two distinct mouse models of ASD through postsynaptic Src and NMDAR activation. Our study suggests that CQ-dependent mobilization of Zn from pre- to postsynaptic sites—not Zn removal after chelation—might be useful in the treatment of ASDs. This unique transsynaptic Zn mobilization is supported by the following findings:
(1) CQ failed to enhance NMDAR function in ZnT3_/_ mice, which lack the presynaptic Zn pool; and (2) Ca-EDTA, a membrane-impermeable Zn chelator that should chelate Zn in the synaptic cleft or extracellular sites, blocked CQ-dependent NMDAR activation.
Finally, our study broadens the therapeutic potential of CQ. CQ has been used as a topical antiseptic or an oral intestinal amoebicide since 1930s, although the latter use has ceased for its controversial association with subacute myelo-optic neuropathy.
Recently, however, CQ-dependent chelation of Zn has been suggested for the treatment of neurological disorders including Alzheimer’s disease67, Parkinson’s disease68 and Huntington’s’ disease. Moreover, PBT2, a second-generation CQ-related compound under clinical trials, seems to be safe and improve cognitive deficits in patients with Alzheimer’s disease.
Therefore, our study is the first to demonstrate the possibility of repositioning of the FDA-approved antibiotic, CQ, to ASDs based on a novel mechanism distinct from chelation. In addition, CQ-dependent trans-synaptic Zn mobilization might also be useful in other psychiatric disorders that are notable for being caused by a decrease in NMDAR function.
In conclusion, our study suggests that trans-synaptic Zn mobilization rapidly improves social interaction in two independent mouse models of ASD through Src and NMDAR activation, and a new therapeutic potential of CQ in the treatment of ASDs.
Shank3 and Autism/Schizophrenia
Shank3, which is found at synapses in the brain, is associated with neuro-developmental disorders such as autism and schizophrenia.
The exact role of Shank3 is very complex and would take a long time fully understand. It particularly affects all the types of glutamate receptor, so the AMPA, NMDA and mGluRs in the diagram below. Note the green circle with zinc, Zn2+.
Shank proteins particularly Shank2 and Shank3 are associated with autism and a Shank dysfunction is even called a “Shankopathy”.
Schematic of the partial Shank protein interactome at the PSD with Shank3 as a model. A more complete list of Shank family interacting proteins is shown in Table 2. Protein domains in Shank family members are similar. Many interacting proteins interact with all three Shank family proteins (Shank1, Shank2, and Shank3) in in vitro assays. The proteins in red font are altered in Shank3 mutant mice.
Here is a science-light article from New Zealand.
Cellular changes in the brain caused by genetic mutations that occur in autism can be reversed by zinc, according to research at the University of Auckland.
Medical scientists at the University’s Department of Physiology have researched aspects of how autism mutations change brain cell function for the past five years.
This latest work - a joint collaborative effort lead by neuroscientist collaborators in Auckland, America and Germany - was published today in the high impact journal, The Journal of Neuroscience.
The study was funded by the Marsden Fund and the Neurological Foundation.
Lead investigator at the University of Auckland, Associate Professor Johanna Montgomery from the University’s Department of Physiology and Centre for Brain Research, says “This most recent work, builds significantly from our earlier work showing that gene changes in autism decrease brain cell communication.”
”We are seeking ways to reverse these cellular deficits caused by autism-associated changes in brain cells," she says. “This study looks at how zinc can alter brain cell communication that is altered at the cellular level and we are now taking that forward to look at the function of zinc at the dietary and behaviour level."
“Autism is associated with genetic changes that result in behavioural changes,” says Dr Montgomery. “It begins within the cells, so what happens at a behavioural level indicates something that has gone wrong at the cellular level in the brain.”
International studies have found that normally there are high levels of zinc in the brain, and brain cells are regulated by zinc, but that zinc deficiency is prevalent in autistic children.
“Research using animal models has shown that when a mother is given a low zinc diet, the offspring will be more likely to display autistic associated behaviours,” she says.
“Our work is showing that even the cells that carry genetic changes associated with autism can respond to zinc.
“Our research has focused on the protein Shank3, which is localized at synapses in the brain and is associated with neuro-developmental disorders such as autism and schizophrenia,” she says.
“Human patients with genetic changes in Shank3 show profound communication and behavioural deficits. In this study, we show that Shank3 is a key component of a zinc-sensitive signalling system that regulates how brain cells communicate.”
“Intriguingly, autism-associated changes in the Shank3 gene impair brain cell communication,” says Dr Montgomery. ”These genetic changes in Shank3 do not alter its ability to respond to zinc”.
“As a result, we have shown that zinc can increase brain cell communication that was previously weakened by autism-associated changes in Shank3”.
“Disruption of how zinc is regulated in the body may not only impair how synapses work in the brain, but may lead to cognitive and behavioural abnormalities seen in patients with psychiatric disorders.”
“Together with our results, the data suggests that environmental/dietary factors such as changes in zinc levels could alter this protein’s signalling system and reduce its ability to regulate the nerve cell function in the brain,” she says.
This has applications to both autism and psychiatric disorders such as schizophrenia.
Dr Montgomery says the next stage of their research is to investigate the impact of dietary zinc supplements to see what impact it has on autistic behaviours.
“Too much zinc can be toxic, so it is important to determine the optimum level for preventing and treating autism and also whether zinc is beneficial for all or a subset of genetic changes that occur in Autism patients.”
Shank3 is a multidomain scaffold protein localized to the postsynaptic density of excitatory synapses. Functional studies in vivo and in vitro support the concept that Shank3 is critical for synaptic plasticity and the trans-synaptic coupling between the reliability of presynaptic neurotransmitter release and postsynaptic responsiveness. However, how Shank3 regulates synaptic strength remains unclear. The C terminus of Shank3 contains a sterile alpha motif (SAM) domain that is essential for its postsynaptic localization and also binds zinc, thus raising the possibility that changing zinc levels modulate Shank3 function in dendritic spines. In support of this hypothesis, we find that zinc is a potent regulator of Shank3 activation and dynamics in rat hippocampal neurons. Moreover, we show that zinc modulation of synaptic transmission is Shank3 dependent. Interestingly, an autism spectrum disorder (ASD)-associated variant of Shank3
(Shank3R87C) retains its zinc sensitivity and supports zinc-dependent activation of AMPAR-mediated synaptic transmission. However, elevated zinc was unable to rescue defects in trans-synaptic signaling caused by the R87C mutation, implying that trans-synaptic increases in neurotransmitter release are not necessary for the postsynaptic effects of zinc. Together, these data suggest that Shank3 is a key component of a zinc-sensitive signaling system, regulating synaptic strength that may be impaired in ASD.
Shank3 is a postsynaptic protein associated with neurodevelopmental disorders such as autism and schizophrenia. In this study, we show that Shank3 is a key component of a zinc-sensitive signaling system that regulates excitatory synaptic transmission.
Intriguingly, an autism-associated mutation in Shank3 partially impairs this signaling system. Therefore, perturbation of zinc homeostasis may impair, not only synaptic functionality and plasticity, but also may lead to cognitive and behavioral abnormalities seen in patients with psychiatric disorders.
Figure 6. Model of zinc-dependent regulation of Shank3 dynamics and activation state. Our data suggest that zinc changes the conformation and association of Shank3 within dendritic spines, resulting in Shank3, which dynamically exchanges between three pools. In pool 1, Shank3 is in an active conformation in the presence of higher zinc (green squares). This conformation assembles into an active signaling complex that includes Homer, AMPARs, and Neuroligin, leading to enhanced synaptic transmission. When zinc levels are low, Shank3 is inactive and resides in two additional pools: one that is rapidly exchanging (red squares) and one that contains oligomerized Shank3 (bound red squares). Oligomerization is potentially mediated by its SAM domain. We propose that, during synaptic transmission, zinc released from vesicles or from intracellular stores could lead to real-time changes in synaptic strength through the recruitment of activated Shank3 into the PSD.
In summary, our studies reveal that Shank3 not only senses changes in postsynaptic zinc, but also is a key component of a zinc sensitive signaling pathway at excitatory synapses. Importantly, zinc homeostasis is disrupted in neuropsychiatric disorders including ASD (Curtis and Patel, 2008; Grabrucker et al., 2011a; Russo and Devito, 2011; Yasuda et al., 2011). Elevation of zinc has been shown to rescue normal social interaction via Src andNMDARactivation in Shank2 and Tbr1 ASD mouse models (Lee et al., 2015), whereas chronic zinc deficiency induces the loss of Shank2/3 and increases the incidence of ASD-related behaviors (Grabrucker et al., 2014). Together with our results, these data suggest that environmental/ dietary factors such as changes in zinc levels could alter the Shank3-signaling system and reduce the optimal performance of Shank3-dependent excitatory synaptic function. Therefore, strategies to activate this zinc-sensitive pathway could potentially restore the functionality of these synapses.
Zinc and Dopamine
I know that some readers of this blog are interested in dopamine.
Zn2+ reverses functional deficits in a de novo dopamine transporter variant associated with autism spectrum disorder
It is clear that zinc can play an important role in autism, but the research has a long way to go to really understand all of the issues.
Impaired zinc homeostasis (equilibrium) is going to cause numerous effects. It will disturb all the glutamate receptors (AMPA, NMDA, mGluRs); in doing so it would disturb the brain’s excitatory-inhibitor balance.
The research from Taiwan suggests that moving zinc from pre- to post-synaptic sites using an old drug called Clioquinol might be useful in the treatment of some autism.
Some research suggests that correcting a low level of zinc, found in a blood test, using a supplement may have a beneficial effect. I suspect the impact is either small or highly variable, but simple to check.
Low levels of zinc seem to be associated by high levels of copper. Supplementing zinc raises the level of zinc and also reduces the level of copper.
Large amounts of supplemental zinc have a paradoxical effect of reducing the level of zinc in the hippocampus.
The real issue is perhaps the transport of zinc within the brain, there are many zinc transporters and it is most likely that the problem in autism is caused by zinc transport rather than a lack of dietary zinc. Faulty zinc transporters are associated with numerous diseases, but only recently has autism research started to move from the simple idea of zinc deficiency to consider the role of specific zinc transporters, like ZIP2 and ZIP4.
Supplementing zinc, along with scores of other things, has long been practiced by alternative therapists in autism. I could not find many reports of significant positive changes.
Hopefully, there will be a human trial of Clioquinol in Taiwan and, if there is, I hope they will check the expression Sonic Hedgehog and Indian Hedgehog.