Stimulating Hypothesis

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Stimulating Hypothesis

The stimulating hypothesis says that the imbalance between inhibitory and excitatory synaptic currents causes ASD.

Estrogens can regulate the expression of glutamic acid decarboxylase, thus modulating GABA signaling, as well as modulating whether GABA is excitatory or inhibitory through the cotransporter KCC2. Androgens can predispose males to GABA mediated excitoxicity. Thus, sex hormones could modulate the excitatory/inhibotyr balance, perhaps sensitizing the male brain to ASD, and play a role in explaining while ASD occurs in males 4 times as often as it occurs in females.

Neural Synchrony and the development of cortical networks

Neural synchronization is imperative in the successful synchronization of different areas of the brain for proper development. Evidence shows that neural synchronization of oscillations is involved in synaptic plasticity. Oscillations during both resting state and cognitive tasks show that gamma oscillations start to appear during childhood and temporal coordination is refined until early adulthood. This co-occurs with changes in the myelination of cortico-cortical connections and the development of GABAergic transmissions.

It may be that abnormal brain maturation during the early prenatal and postnatal periods results in cortical circuits which cannot support the frequency high frequency oscillations that appear typically during infancy. As a result, the temporal precision that is required for specific firing patterns during development is disturbed and the activity dependent selection of specific cortical circuits during development is absent for children with ASD. 3

Brain MRI T1 movie.gifNeuroimaging

Anaphase IF.gifGenetics

A central component in this theory are the variants in Neuroligins and Neurexins that have been found in ASD probands. Neuroligins and Neurexins are likely to be the centrally organizing molecules for excitatory glutamatergic and inhibitory GABAergic synapses in the mammalian brain. Studies have shown that mutant mice with the R451C Nlgn3 mutation have increased GABAergic synapses and inhibitory currents. In addition, MeCP2 knockout mice, Caps2 knowckout mice, mice exposed to prenatla valproate treatment, and many other models have imbalances of inhibition and excitation.1

It is unknown whether these changes represent changes in synaptic signaling, or are just responses from a change in homeostasis. However, given that many of the susceptibility genes in ASD affect synapse formation signaling. Additionally, several of the genes also affect cortical interneurons.2

Animal Models

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1. Kelleher RJ 3rd et. al. The autistic neuron: troubled translation?Cell. 2008 Oct 31;135(3):401-6. PMID 18984149

2. Rubenstein JL.Three hypotheses for developmental defects that may underlie some forms of autism spectrum disorder.Curr Opin Neurol. 2010 Apr;23(2):118-23. PMID 20087182

3. Uhlhaas PJ et. al. Neural synchrony and the development of cortical networks.Trends Cogn Sci. 2010 Feb;14(2):72-80. PMID 20080054