Disorders of the Synapse: Fragile X, Rett Syndrome and Autism

For children who were eight in 2022, the US Centers for Disease Control and Prevention estimated that about 1 in 31 in the communities it monitors had been identified as autistic. No blood test, scan or gene test made a single one of those diagnoses.

Autism is diagnosed from behaviour. Yet it runs strongly in families, and the genes found so far point again and again at one structure: the synapse. That raises a developmental question in the form the professor asks it at the end of his course: “Where might these developmental mechanisms fail in autism spectrum disorders?” Neurons must gather in the right places, send axons to the right targets, win trophic support, and then build, prune and maintain their synapses. A change at any step could alter a circuit. This lesson takes two single-gene conditions in which the failing step can be named, fragile X syndrome and Rett syndrome, and then asks what animal models of maternal infection add.

A note on words. Many autistic people prefer identity-first language (“autistic people”), and some prefer “people with autism”; this lesson mostly uses the first. Autism is a difference in how a brain develops, and the biology below is about mechanism, not about fixing people.

The idea: one diagnosis defined by behaviour, many genetic routes into it

In 2013 the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) merged autistic disorder, Asperger’s disorder and related categories into one diagnosis, autism spectrum disorder. It rests on two areas of behaviour: differences in social communication and interaction, and restricted or repetitive behaviours and interests, present from early childhood. Signs are often noticed in the second year of life. “Spectrum” means that support needs range widely, from people who need help every day to people who need little.

Measured prevalence has risen. A CDC report in 2014 gave 1 in 68 for children who were eight in 2010; the report published in 2025 gave 1 in 31 for 2022. Much of the rise is generally attributed to broader criteria, more screening and better access to diagnosis. Boys were identified more than three times as often as girls in the 2022 data.

Twin studies estimate heritability at roughly 60 to 90 percent, meaning that most of the variation in who is diagnosed tracks genetic variation. No single gene explains it. Most of the genetic contribution is thought to come from many common variants, each with a tiny effect, while rare new mutations with large effects explain a smaller share of cases. Large sequencing studies have now named about a hundred genes with strong evidence. Two groups stand out: genes for synaptic proteins and genes that regulate chromatin and transcription.

The synaptic group fits the professor’s question. Neurexins on the sending side bind neuroligins on the receiving side and help specify a synapse (see CNS synapses); rare variants in NRXN1, NLGN3 and NLGN4X have been found in some autistic people. SHANK3 is a scaffold protein that organizes receptors in the postsynaptic density of excitatory synapses. Mice lacking Shank3 show altered synapses in the striatum and groom themselves excessively. Other syndromes act on growth signalling at synapses: TSC1, TSC2 and PTEN mutations all raise mTOR activity (see mTOR and AMPK), and each carries a higher chance of autism. Pruning may matter too, through microglia and complement (see microglia and complement).

Fragile X: a synapse that makes too much protein

Fragile X syndrome is the most common inherited cause of intellectual disability, and many people with it, more often males, are also autistic. Its cause is a repeat of three bases, CGG, near the start of the FMR1 gene on the X chromosome. Most people have fewer than about 45 copies. Between about 55 and 200 copies is a premutation, which can grow when a mother passes it on. Above about 200 copies, the gene’s control region becomes methylated and the gene is silenced. The protein, FMRP, is not made.

FMRP binds RNA. In neurons it travels with hundreds of mRNAs, many encoding synaptic proteins, and holds back their translation. Dendrites carry their own ribosomes, so synapses can make protein locally within minutes of a signal. FMRP is a brake on that local synthesis.

One signal that releases the brake comes through mGluR5, a metabotropic glutamate receptor (a G protein-coupled receptor; see GPCRs and G proteins). In the hippocampus, activating group I mGluRs makes synapses weaken for hours, a long-term depression (LTD) that needs new protein. In 2002 Kimberly Huber, Mark Bear, Stephen Warren and colleagues found this mGluR-LTD exaggerated in Fmr1 knockout mice. Dendritic spines in these mice, and in brain tissue from affected people, are often long and thin, like immature spines.

In 2004 Bear, Huber and Warren proposed the mGluR theory: without FMRP, mGluR5 signalling drives too much protein synthesis, and many features of the syndrome follow. In 2007 Gül Dölen and Bear tested it by breeding fragile X mice with only one working copy of the mGluR5 gene. Several traits moved toward those of typical mice, including protein synthesis, spine density and seizures triggered by loud sound.

Drugs that block mGluR5 then went into people. Placebo-controlled trials of two such drugs, mavoglurant (reported in 2016) and basimglurant (2018), in adolescents and adults with fragile X syndrome did not improve the main behavioural measures. The reasons are still argued: patients were older than the treated mice, behaviour scales may change too slowly, tolerance may develop, and a mouse is not a person. The theory still explains a great deal of mouse biology. It did not yet transfer to a treatment.

Rett syndrome: a circuit that needs MeCP2 to keep running

In 1966 the Austrian paediatrician Andreas Rett described girls who seemed to develop typically for many months and then lost purposeful hand use and speech, made repetitive hand movements, and had slowed head growth. Seizures, breathing irregularities, scoliosis and sleep problems are common. In 1999 the laboratory of Huda Zoghbi at Baylor College of Medicine, with Uta Francke’s group, found that mutations in MECP2 cause most cases.

MECP2 encodes methyl-CpG-binding protein 2, MeCP2, which binds DNA where cytosines carry methyl groups. It is abundant in neurons and is thought to help set the level at which many genes are expressed, often by recruiting a co-repressor complex.

The gene is on the X chromosome, which shapes who is diagnosed. In each cell of a female embryo one X is switched off at random, so a girl with one mutant copy is a mosaic: some neurons use the working copy and others the mutant one. Most mutations arise new, most often in the father’s sperm, and a father passes his X only to daughters. Boys with a severe mutation have no working copy and usually have a different, severe course from early infancy. Too much MeCP2 is also harmful: duplication of MECP2 causes a separate syndrome in males.

Mice lacking Mecp2 appear typical for several weeks and then develop tremor, breathing changes and reduced movement. Their neurons do not die in large numbers. They are smaller and more tightly packed, with simpler dendrites.

Design problem

Suppose Rett syndrome comes from circuits built wrongly during development. Using mice in which Mecp2 is silent but can be switched on with a drug, what should happen when MeCP2 is restored in adult mice that already have symptoms? What result would show instead that the circuit is built but needs MeCP2 to keep working?

”Not a good time for the immune system to act up”

Genes are not the whole story. In people, rubella infection during pregnancy, mainly from the epidemic of the mid-1960s, was associated with autism in the children. In a Danish registry study, hospital admission for a viral infection in the first trimester was associated with a roughly threefold higher rate of autism diagnosis in the child. These are associations, and most children of mothers with infections are not autistic. They concern infection, not vaccines: vaccines do not cause autism, and rubella vaccination prevents congenital rubella.

Rodent models test the idea directly. Poly(I:C), a synthetic double-stranded RNA, mimics a viral infection and sets off an immune response with no virus present. In 2007 Stephen Smith, Paul Patterson and colleagues gave it to pregnant mice and found that the offspring behaved differently as adults; a single dose of the cytokine IL-6 had a similar effect, and blocking IL-6 prevented it. In 2016 Gloria Choi, Jun Huh and colleagues traced a step further: maternal T cells making IL-17a were required, and offspring had patches of disorganized cortex.

Monkeys bring the model closer to people. Researchers at the University of California, Davis gave pregnant rhesus monkeys antibodies purified from mothers of autistic children, and the offspring showed more repetitive movement and hyperactivity than controls. These studies used small numbers of animals and need cautious reading.

All of this rests on the professor’s question: “How can we recapitulate and evaluate complex behaviors?” In mice the usual tests score time spent near a stranger in a three-chamber box, ultrasonic calls, marble burying and grooming. They measure mouse behaviour. A mouse that buries marbles is not autistic, and a cytokine that changes its behaviour has not been shown to cause autism in a child. What these models can do is identify a mechanism, such as a maternal cytokine acting on the developing cortex during a window of pregnancy, that human studies can then look for.