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Autism may begin at earliest brain development

Brains of mice with autism-like symptoms develop neural defects when their first brain circuits take shape.


Autism is not a single condition, but a spectrum of disorders that affect the brain's ability to perceive and process information. Recent research suggests that too many connections in the brain could be at least partially responsible for the symptoms of autism, from communication deficits to unusual talents.

New research from the University of Maryland (UMD) suggests that this overload of connections begins early in mammalian development, when key neurons in the cerebral cortex begin to first form circuits.


By pinpointing where and when autism-related neural defects first emerge in mice, the study results could lead to a stronger understanding of autism — including possible early interventions.


Researchers outline their findings in a paper published January 31, 2017 in the journal Cell Reports.

"Our work suggests that the neural pathology of autism manifests in the earliest cortical circuits, formed by a cell type called subplate neurons," said UMD Biology Professor and senior study author Patrick Kanold PhD.


Subplate neurons form the first connections in the developing cerebral cortex — the outer part of the mammalian brain controlling perception, memory and, in humans, higher functions such as language and abstract reasoning. Interconnected subplate neurons form a network of scaffolding thought to support other neurons growing later.


"The cortex is a very important region in the adult human brain that undergoes a complex, multi-stage development process," said Daniel Nagode, a former postdoctoral researcher at UMD and lead author of the study. "Because our findings implicate the earliest stages of cortex circuit formation in a mouse model, they suggest that the pathological changes leading to autism might start before birth in humans."

To study the relationship between autism and subplate neuron development in mice, Kanold, Nagode and their collaborators injected the drug valproic acid (VPA) into mother mice on day 12 of their 20-day gestation. VPA has a known link to autism in humans and also induces autism-like cognitive and behavioral abnormalities in mice. While normal newborn mouse pups will emit frequent, high-pitched noises when they are separated from their littermates, VPA-treated pups do not.

Researchers then used a laser scanning photostimulation technique to map connections between individual subplate neuron cells in the brains of the mouse pups. Within the first week after birth, the VPA-dosed mice showed some patches of "hyperconnected" subplate neurons. In contrast, control mouse pups dosed with plain saline solution showed normal connections throughout their cortical tissue.


Ten days after birth, patches of hyperconnected subplate neurons had grown more widespread in VPA-dosed pups compared with control pups.

As subplate neurons help lay the foundation for cortical development in all mammalian brains, a thicket of hyperconnected subplate neurons could remain as permanent hyperconnections.


If the same dynamic plays out in human brains, hyperconnections in the developing cortex could result in the neural pathologies observed in human autism, Kanold said. In mice as well as in humans, the critical window of time when subplate neurons develop is very short.

"The timing of the effects is important. The hyperconnectivity in VPA pups occurs only in small patches a few days after birth," Nagode explains. "But after 10 days, the hyperconnectivity becomes much more widespread."

In mice, subplate neurons develop mostly after birth. Eventually, they die off and disappear, as other neural circuits take their place. However, in humans the first subplate neuron connections form in the second trimester. By the time of birth, most subplate neurons have already disappeared.


"The fetal brain is not just a small adult brain, and these subplate neurons are the major difference. There may, in fact, be other developmental disorders we can tackle using this information."

Daniel Nagode PhD, former postdoctoral researcher at University of Maryland, USA, and lead author of the study.


Abstract
Highlights
•Prenatal VPA exposure alters excitatory and inhibitory connectivity in the subplate
•VPA exposure induces laminar-dependent hyperconnectivity to subplate
•Fine-scale spatial analysis reveals “patches” of altered connectivity after VPA
•VPA alters excitatory-inhibitory balance of subplate circuits

Summary
Autism spectrum disorder (ASD) involves deficits in speech and sound processing. Cortical circuit changes during early development likely contribute to such deficits. Subplate neurons (SPNs) form the earliest cortical microcircuits and are required for normal development of thalamocortical and intracortical circuits. Prenatal valproic acid (VPA) increases ASD risk, especially when present during a critical time window coinciding with SPN genesis. Using optical circuit mapping in mouse auditory cortex, we find that VPA exposure on E12 altered the functional excitatory and inhibitory connectivity of SPNs. Circuit changes manifested as “patches” of mostly increased connection probability or strength in the first postnatal week and as general hyper-connectivity after P10, shortly after ear opening. These results suggest that prenatal VPA exposure severely affects the developmental trajectory of cortical circuits and that sensory-driven activity may exacerbate earlier, subtle connectivity deficits. Our findings identify the subplate as a possible common pathophysiological substrate of deficits in ASD. Keywords: subplate, autism, cortex, development, valproate

The research paper, "Abnormal development of the earliest cortical circuits in a mouse model of Autism Spectrum Disorder," Daniel Nagode, Xiangying Meng, Daniel Winkowski, Ed Smith, Hamza Khan-Tareen, Vishnupriya Kareddy, Joseph Kao, and Patrick Kanold, was published January 31, 2017 in the journal Cell Reports.

This work was supported by the National Institutes of Health (Award Nos. R01DC009607, R01GM056481, CEBHT32DC00046 and CEBHF32DC014887). The content of this article does not necessarily reflect the views of this organization.

University of Maryland
About the College of Computer, Mathematical, and Natural Sciences
The College of Computer, Mathematical, and Natural Sciences at the University of Maryland educates more than 7,000 future scientific leaders in its undergraduate and graduate programs each year. The college's 10 departments and more than a dozen interdisciplinary research centers foster scientific discovery with annual sponsored research funding exceeding $150 million.
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Subplate neurons form a network of interconnected scaffolding believed to support other neurons
developing later
. However, if gone awry, hyperconnected subplate neurons could lead to autism.
Image Credit: Patrick Kanold PhD, senior author UMD

 


 


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