Several autism-risk genes affect the function of chemical synapses. The relevant literature is vast. Here we begin with studies of the balance between excitation and inhibition, synaptic plasticity, neurogenesis and neuromodulators.

Excitatory/inhibitory (E/I) balance

This balance is determined in part by the number and function of excitatory and inhibitory synapses, the excitability of input and output neurons and the ability of microcircuits to compensate for synaptic alterations, known as synaptic homeostasis.

1. Genes encoding proteins that affect neurotransmitter release, receptor function and inactivation have been implicated in autism.
2. Evidence for increased excitatory drive is based largely on the frequency and amplitude of spontaneous and action-potential-evoked excitatory synaptic potentials. Most studies have focused on isolated brain slices, and most slices have been prepared from the hippocampus.
   1. Increased frequencies and amplitudes of excitatory synaptic potentials have been observed in mouse models bearing human mutations in genes such as NLGN3, SHANK3, TSC1 and TSC2.
   2. Mouse models of fragile X syndrome exhibit a higher density of dendritic spines in basal dendrites of cortical pyramidal neurons.
   3. Reduction in glutamate-receptor activity by genetic or pharmacological means reverses cellular and behavioral deficits in fragile X mouse models.
   4. Perturbation of E/I balance using optogenetic techniques leads to changes in social behavior in mice.
   5. Genes encoding voltage-gated calcium, sodium and potassium channels that likely contribute to E/I balance have been implicated in autism.
3. Evidence for reduced synaptic inhibition is based on assays of function mediated by gamma-aminobutyric acid (GABA).
   1. Mouse models of Rett syndrome and others bearing human autism risk variants show a decrease in parvalbumin-stained GABAergic interneurons.
   2. Postmortem tissue samples from the cerebella of individuals with autism show reductions in glutamic acid decarboxylase, the rate-limiting enzyme in GABA synthesis, and in the number of Purkinje cells.
   3. GABA levels are low in several cortical areas of individuals with autism as measured by magnetic resonance spectroscopy.

1. Is E/I imbalance evident in local circuits in vivo in response to natural stimuli?
2. When do E/I imbalances first appear?
3. How do compensatory changes in synaptic function alter the initial perturbation in E/I balance?
4. Does the shift in the role of GABA from excitatory neurotransmission to inhibitory neurotransmission during early development play a role in autism?
5. What are the proximate causes of E/I imbalance?
6. How do E/I imbalances affect local microcircuits and long-distance connections?
7. Can E/I balance be restored pharmacologically (see “Therapeutics”) or genetically?

Another hypothesis, not entirely independent of the first, suggests that autism-related changes in synaptic transmission depend on neuronal activity, or experience. Short-term (seconds to minutes) and long-term (hours to days) mechanisms have been implicated.

1. Genes that regulate activity-dependent synaptic plasticity, including ARC, have been implicated in autism.
2. Variants of the UBE3A gene are associated with reduced activity-dependent synaptic plasticity.
3. The critical period in the visual system (plasticity of ocular dominance columns) is exaggerated in mice that model fragile X syndrome.
4. Fragile X mice show reduced levels of long-term depression and also reduced plasticity of the visual cortex following monocular occlusion. Antagonists of mGluR5 can reverse the deficit in long-term depression and in cortical plasticity.
5. NLGN mouse models show altered long-term potentiation.
6. Synaptic plasticity in the hippocampus is altered in mice that lack SHANK2.
7. Short-term synaptic plasticity (facilitation and depression) is altered in mice bearing 22q11.2 deletions and other mouse models.
8. BDNF has been implicated in deficits in activity-dependent plasticity in models of autism.

1. What is the influence of neuronal activity on the expression of autism-risk genes?
2. What molecular pathways are involved in changes in synaptic plasticity and their reversal?
3. Do reported variants in genes that regulate autophagy, or cellular self-ingestion, play a role in synapse elimination?
4. Can the relative influence of short-term synaptic plasticity (facilitation, depression) be distinguished from long-term synaptic plasticity in maintaining local circuit function and relevant behaviors?

Hypotheses about altered brain development in individuals with autism involve changes in the birth and programmed cell death of neurons and glia, altered fate determination and aberrant cell migration.

1. Brain size, measured by head circumference and more directly by magnetic resonance imaging, is increased in about 20 percent of pre-teenage children with autism.
2. The number and size of neurons in gray matter, as well as the number of axons and glia in the underlying white matter, is increased in autopsy specimens from individuals with autism.
3. Subcortical nuclei, including those in the amygdala and cerebellum, are also enlarged.
4. Head size is large in mouse models of autism (PTEN and others), and large displaced neurons are observed.

1. Are changes in brain size due to excess proliferation of neuronal precursors or the failure of normal regressive events such as synapse elimination, axon retraction and programmed nerve-cell death?
2. Are changes in fate determination evident in animal models of autism?
3. What roles do glia (astrocytes, oligodendrocytes and microglia) play in the axonal and synaptic deficits associated with autism?
4. Are changes in neuron number and brain volume associated with changes in circuit function?
5. Do other animal models of autism, including zebrafish, Drosophila melanogaster, and Caenorhabditis elegans, offer unique advantages in studies of synaptic plasticity?

Certain transmitters and hormones that modulate synaptic transmission have been implicated in autism.

1. Serotonin is increased in the serum of individuals with autism. Positron emission tomography studies suggest that serotonin synthesis is impaired in children with autism, particularly in the frontal cortex, thalamus and cerebellum.
2. Acetylcholine binding to nicotinic and muscarinic receptors is reduced in the parietal and frontal cortices of postmortem brains from individuals with autism. The alpha-7 acetylcholine nicotinic receptor gene is included in the 15q13.3 microdeletion.
3. Melatonin secretion is reduced in many individuals with autism, and the deficit may be due to a deficiency in ASMT, the gene that encodes for the rate-limiting enzyme in melatonin synthesis.
4. Children with autism experience reduced rapid-eye-movement sleep. Melatonin treatment improves their sleep latency and total sleep time.
5. Genetic variants of the oxytocin receptor and of CD38, a protein that modulates the secretion of oxytocin, have been noted in individuals with autism.

1. Do any of the modulators listed above suggest targets for drug therapy?

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