Understanding the roots of autism

In Fragile X syndrome (FXS), the most common cause of autism, sensory signals from the outside world are integrated differently, causing them to be underrepresented by cortical pyramidal neurons in the brain. That’s according to a new study led by Université de Montréal (UdeM) Professor Roberto Araya and published in the journal PNAS.

Autism is characterised by a wide range of symptoms that may stem from differences in brain development. With advanced imaging tools and the genetic manipulation of neurons, researchers at the UdeM-affiliated CHU Sainte-Justine Research Centre were able to observe the functioning of individual neurons; specifically, pyramidal neurons of cortical layer 5 — one of the main information output neurons of the cortex. The researchers found a difference in how sensory signals are processed in these neurons.

“Previous work has suggested that FXS and autism spectrum disorders are characterised by a hyperexcitable cortex, which is considered to be the main contributor to the hypersensitivity to sensory stimuli observed in autistic individuals,” Araya said.

“To our surprise, our experimental results challenge this generalised view that there is a global hypersensitivity in the neocortex associated with FXS,” added Diana E Michell, first co-author of the study. “They show that the integration of sensory signals in cortical neurons is underrepresented in a murine model of FXS.”

The researchers’ tree image (below) helps to illustrate the morphology and function of pyramidal neurons in FXS. These neurons are one of the main integrators of information in the cerebral cortex, with long ‘branches’ and ‘roots’ representing dendrites. The small ‘leaf-like’ projections are the dendritic spines, where the excitatory synapses are located — connecting one neuron to another. The blurred sections of the image illustrate the altered integration and perception of sensory information from the outside world discovered by the UdeM team.

Image credit: Roberto Araya and Soledad Miranda-Rottmann.

An absent protein

A protein called FMRP that is absent in the brains of people with FXS modulates the activity of a type of potassium channel in the brain. According to the research group’s work, it is the absence of this protein that alters the way sensory inputs are combined, causing them to be underrepresented by the signals coming out of the cortical pyramidal neurons in the brain.

Soledad Miranda-Rottmann, also first co-author of the study, attempted to rectify the situation with genetic and molecular biology techniques. “Even in the absence of the FMRP protein, which has several functions in the brain, we were able to demonstrate how the representation of sensory signals can be restored in cortical neurons by reducing the expression of a single molecule,” she said.

The phenomenon the team observed not only provides insight into the mechanism of FXS at the cellular level, but also opens the door to new targets for therapeutic strategies “to offer support to those with FXS and possibly other autism spectrum disorders to correctly perceive sensory signals from the outside world at the level of pyramidal neurons in the cortex,” Araya said.

“Even if the overrepresentation of internal brain signals causing hyperactivity is not addressed, the correct representation of sensory signals may be sufficient to allow better processing of signals from the outside world and of learning that is better suited to decision-making and engagement in action.”

Top image credit: iStock.com/Irina_Geo