Startled fish help sound out sensory overload in autism

People get used to things: Sights, sounds and whatever other stimuli there may be, our brains adapt to them over time. The technical term for this is habituation.

There is some evidence that people with autism are less able to habituate than their peers¹. This may explain the sensory hypersensitivities some people with the disorder experience².

A study published this past March in Neuron suggests that mutant fish can help scientists understand whether and how habituation is altered in autism. The study provides some of the first molecular insights into neural habituation, with several intriguing ties to autism³. In fact, some autism-linked genes might contribute to problems adapting to sensory stimuli.

By day 5 of their lives, zebrafish larvae startle in response to loud noises. But if the sound occurs at regular intervals, the fish get used to it. The neurons in the brain slow their responses: They habituate.

The researchers exposed male zebrafish to a mutagen. They then bred the fish and measured habituation in the larvae. Basically, they went fishing for mutations that disrupt habituation. They identified 14 mutants whose larvae show less than half the normal habituation response.

They sequenced the genomes of two of the mutant strains to home in on the mutations. One of the strains has a mutation that truncates an enzyme called PAPP-AA. This enzyme is expressed in several parts of the circuit responsible for the acoustic startle reflex in zebrafish. However, this circuit appears to be anatomically intact in themutants, so the mutation may affect the circuit in a subtle way.

Sensitivity genes:

PAPP-AA cleaves insulin-like growth factor (IGF) binding protein 4, boosting the availability of IGF, a protein that nurtures neurons.

In a series of experiments, the researchers showed that introducing normal PAPP-AA into thelarvae of the mutant fish restores normal habituation. But a version of PAPP-AA that lacks the normal enzyme’s cleaving ability cannot do so, showing that the splitting of the IGF binding protein is important to the circuit’s operation.

The researchers also found that a drug that activates an enzyme called AKT, which IGF signaling normally stimulates, can restore normal habituation at day 3 to 5 of larval development in the PAPP-AA mutants. This finding provides further support for the importance of the IGF signaling pathway in habituation.

These findings are from fish, not people. But it’s reasonable to assume that these processes are to some extent common to all vertebrates. And although the paper makes no mention of autism, it provides a basis for exploring the mechanisms that may link the disorder to habituation.

For instance, AKT and another molecule involved in IGF signaling, called PI3K, participate in pathways that have been firmly implicated in the autism-linked disorders Cowden syndrome and tuberous sclerosis. Similarly, a study published earlier this year identified de novo, or spontaneous, mutations in genes involved in IGF signaling in the Simons Simplex Collection⁴. The collection is a database of samples and information from families that have one child with autism and unaffected parents and siblings. (It is funded by the Simons Foundation, SFARI.org’s parent organization.)

These observations suggest that some of the genetic mutations implicated in autism may directly lead to habituation problems.

It’s also worth noting that early-stage clinical trials of IGF-1 in two other autism-linked disorders, Rett syndrome and Phelan-McDermid syndrome, have yielded promising results^5,6. If individuals with these syndromes show abnormal habituation, it may be worth considering ways to measure sensory adaptation as an outcome in future trials.

To propose yet one more potential connection between this habituation pathway and autism, PAPP-AA activity requires the presence of zinc. There is at least some evidence implicating zinc deficiency in autism risk.

A paper published last month in Nature Communications reported that clioquinol, a drug that boosts zinc levels at synapses, the junctions between neurons, improves social interaction in two mouse models of autism⁷. One wonders, again, whether it would be worth examining habituation in these mice.

Finally, there are 12 additional habituation mutants uncovered by this study whose genetic basis is as yet unknown. It will be quite interesting to see whether these other mutants implicate genes or biological processes known to be involved in autism.

Alan Packer is senior scientist at the Simons Foundation Autism Research Initiative.

References:

1. Kleinhans N.M. et al. Am. J. Psychiatry 166, 467-475 (2009) PubMed

2. Sinha P. et al. Proc. Natl. Acad. Sci. USA 111, 15220-15225 (2014) PubMed

3. Wolman M.A. et al. Neuron 85, 1200-1211 (2015) PubMed

4. Krumm N. et al. Nat. Genet. 47, 582-588 (2015) PubMed

5. Khwaja O.S. et al. Proc. Natl. Acad. Sci. USA 111, 4596-4601 (2014) PubMed

6. Kolevzon A. et al. Mol. Autism 6, 31 (2015) PubMed

7. Lee E.-J. et al. Nat. Commun. 6, 7168 (2015) PubMed