Protein mutations linked to autism

[S.A.M.]

Scientists have discovered how mutations in two key proteins may lead to autism.

Neuroligins enhance synapse formation in vitro, but surprisingly are not required for the generation of synapses in vivo. We now show that in cultured neurons, neuroligin-1 overexpression increases excitatory, but not inhibitory, synaptic responses, and potentiates synaptic NMDAR/AMPAR ratios. In contrast, neuroligin-2 overexpression increases inhibitory, but not excitatory, synaptic responses. Accordingly, deletion of neuroligin-1 in knockout mice selectively decreases the NMDAR/AMPAR ratio, whereas deletion of neuroligin-2 selectively decreases inhibitory synaptic responses. Strikingly, chronic inhibition of NMDARs or CaM-Kinase II, which signals downstream of NMDARs, suppresses the synapse-boosting activity of neuroligin-1, whereas chronic inhibition of general synaptic activity suppresses the synapse-boosting activity of neuroligin-2. Taken together, these data indicate that neuroligins do not establish, but specify and validate, synapses via an activity-dependent mechanism, with different neuroligins acting on distinct types of synapses. This hypothesis reconciles the overexpression and knockout phenotypes and suggests that neuroligins contribute to the use-dependent formation of neural circuits.

http://www.neuron.org/content/article/abstract?uid=PIIS0896627307004096&highlight=kavalali

The proteins - neuroligin-1 and neuroligin-2 - create a physical bridge at the junction - or synapse - of nerve cells, enabling them to make connections with others.

In studies on rats the researchers showed that raising levels of both proteins in nerve cells led to the creation of extra synapses.

Neuroligin-1 was associated with excitatory connections and neuroligin-2 with inhibitory connections.

When they introduced a mutant form of neuroligin-1 thought to be carried by some people with autism the number of synapses fell dramatically - and the cells became significantly less excitable.

Infants are born with far more synapses than survive to adulthood. Active synapses proliferate during development, but inactive synapses are culled.

The latest research suggests that carrying a mutant form of neuroligin-1 may depress the number of synapses that make it into adulthood.

This could hamper the ability of nerve cells to make the usual connections, and lead to the deficits seen in people with autism.

It affects the way a person communicates and interacts with other people.
http://news.bbc.co.uk/2/hi/health/6221064.stm