While there are many theories on this, I found the glutamate and immune activation connection to be the most interesting. Often you will hear children with autism have experienced some sort of trauma (prematurity, stroke, etc.) or substantial changes to immune function, leading to immune activation (vaccines, illness, and it is now linked that mothers immune activation can trigger immune activation within the fetus, and so on) that parents believe may have triggered or caused their autism. Both trauma and immune activation cause an increase in glutamate. “It was initially thought that autistic children had fewer glutamate receptors, but subsequent studies, including one from the prestigious journal Neurology published in 2001, showed that autistic children, in fact, have more glutamate receptors than normal controls. Furthermore, they are genetically predisposed to have more. So autism is another hyper-glutamate condition.” http://nancymullanmd.com/glutamate-and-gaba-balance/. Excess glutamate his behind the majority of autism symptoms and is believed to be a primary underlying factor in autism. So in considering this, why are more makes affected with autism? Thought provoking.
Is it possibly because estrogen protects against glutamate?
“Estrogen protects primary cortical neurons from glutamate toxicity” https://www.sciencedirect.com/science/article/abs/pii/0304394096127609
“Estrogen protects against the detrimental effects of repeated stress on glutamatergic transmission and cognition”.
There is also this from the brilliant, Dr. Russell Blaylock……
“One of the enigmas of autism is why it occurs in males more often than females. Actually there are a number of toxins that have this gender selectivity. Studies have shown, for example, that both mercury and monosodium glutamate (MSG) have greater neurotoxicity in males than females. The reason appears to be the enhancing effect of testosterone on both substances’ toxicity. Glutamate is the most abundant neurotransmitter in the brain and operates through a very complex series of receptors (3 major inotropic receptors- NMDA, AMPA and kainite receptors, and 8 metabotropic receptors). As stated, the presence of glutamate outside brain neurons, even in very small concentrations, is brain cell toxic. Because of this, the brain is equipped with a very elaborate series of mechanisms to remove glutamate quickly, primarily by utilizing glutamate uptake proteins (EAAT1-5). Mercury, aluminum, free radicals, lipid peroxidation products and inflammatory cytokines can easily damage these. One of the important ways glutamate regulates neuron function is by allowing calcium to enter the cell and by the release of calcium within cell storage depots. When calcium (glutamate operated) channels are opened, the calcium flows in as a wave of concentrated calcium. These are referred to a calcium waves or oscillations. They regulate a number of neuron functions, one of which plays a vital role in brain development. During brain development, the future neurons are lined up along membranes within the core of the undeveloped brain. These cells must migrate outwardly to reach their final destination and they do so by guided chemical signals mainly released by microglia and astrocytes. These trillions of connections also develop during a process called synaptogeneis, and use many of the same signals.
Studies have shown that the calcium waves cause developing brain cells to migrate, which is essential for development of the brain (it forms the architectonic structures and functional columns of the brain). Interestingly, testosterone also affects embryonic brain cell migration by regulating calcium waves, and mercury, probably by stimulating glutamate release, does the same thing. Estrogen reduces calcium oscillations and stops the migration. Other chemical signals in the brain also play a role (reelin). If calcium oscillations are not properly regulated, that is- there are too many calcium oscillations, the brain develops abnormally. Testosterone and glutamate have an additive effect on these calcium waves. In this way, testosterone enhances the damaging effect of excessive glutamate and mercury. Studies have shown that higher doses of MSG during brain formation can cause abnormalities of brain development that closely resemble mercury poisoning and the toxic effects of high levels of inflammatory cytokines. Interestingly, vaccination has been shown to significantly increase the toxicity of several other neurotoxins, so much so that they can trigger brain cell destruction or synaptic loss even when subtoxic concentrations of the toxicants are used. Testosterone aggravates this toxicity as well.
Studies of autistic children show an elevated level of androgens in most, even in female autistic children. In general, androgens, such as testosterone, enhance neurological injury and estrogens tend to be protective of the brain.” http://www.russellblaylockmd.com/
Is it possibly because males have higher concentrations of microglia earlier in life compared to females, making them prone to having high levels of glutamate earlier in life?
What are microglia? Microglia are a type of glial cell located in the brain and the spinal cord. They act as the first and main* form of immune defense in protection against foreign invaders in the central nervous system (CNS). When the microglial are chronically activated (either from a single stimuli or multiple stimuli exposure such as vaccines or chronic underlying infections) they start the inflammatory process, result in disruption of brain function, neuronal loss, and send a surge of damaging cytokines and excitiotoxic levels of glutamate. In other words, microglia when activated, signal additional glutamate. With higher levels of glutamate, cells adapt by creating additional glutamate receptors, and the more glutamate receptors, the more sensitive to glutamate you are. With males having an increased concentration of microglial, they are more vulnerable to the damages associated with immune activation. Here are some highlights from published articles that may help explain the connection:
“Males have overall more microglia early in postnatal development (postnatal day (P) 4), whereas females have more microglia with an activated/amoeboid morphology later in development, as juveniles and adults (P30-60). Finally, gene expression of a large number of cytokines, chemokines and their receptors shifts dramatically over development, and is highly dependent upon sex.”https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3296888/
“The fact that microglia are present in the neonatal brain so early in development means that microglia mature alongside neurons, which supports the idea that microglia are crucial mediators of CNS wiring.” “Microglial Function across the Spectrum of Age and Gender” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372577/