Home > Science > The Neural Cell Adhesion Molecule NrCAM Controls Neural Circuitry Relevant to Autism-Related Sensory and Social Deficits

The Neural Cell Adhesion Molecule NrCAM Controls Neural Circuitry Relevant to Autism-Related Sensory and Social Deficits

This guest post is by Patricia F. Maness, PhD, Professor, Department of Biochemistry, University of North Carolina School of Medicine, Chapel Hill, NC (pictured front row, first from left).

The ability to process sensory information through vision, touch, and hearing has long been noted to be compromised in people with autism spectrum disorders (ASDs).  Some individuals are overly sensitive to certain types of sensory information whereas others may have difficulty integrating information from different modalities.  The exact neural circuits that are dysfunctional that could contribute to these difficulties remain obscure. Neurons from sensory organs such as eyes, skin, and ears, and muscles send information from the environment to a relay center of the brain called the thalamus, where sensory and motor thalamic nuclei are located. Thalamocortical neurons in each of these nuclei transfer partly processed information to final destinations in distinct regions of the cerebral cortex (visual, somatosensory, auditory, and motor areas) to process the information in greater detail. Understanding these circuits and how different genes guide their appropriate development is essential to solving the puzzle of sensory processing differences in autism.

In an important new publication [2], scientists report that a gene, Neuron/Glia-related Cell Adhesion Molecule, or “NrCAM” may play a role in sensory processing difficulties.  Scientists were able to “knockout” this gene in mice and found that this caused groups of somatosensory and motor thalamocortical neurons to incorrectly connect with the visual cortex[1]. Moreover, NrCAM knockout mice developed abnormal visual cortical responses, manifested by decreased visual acuity and altered binocular vision. During embryonic development NrCAM guides thalamocortical axons from the thalamus to their targets in the cortex.  By forming a complex with a receptor (Neuropilin-2), together with a secreted guidance molecule (Semaphorin3F), NrCAM acts as a neural signal directing the way for axons of the neurons to leave the thalamus.

Interestingly, genetic differences at the sites which encode parts of this signaling complex have been independently associated with autism [2-5]. Taken together, these results show that NrCAM is required for development of proper thalamocortical connectivity, and suggest that the aberrant projection of thalamic axons to the visual cortex in NrCAM knockout mice may impair visual processing.

Since social deficits and resistance to change are common features in ASDs, the NcCAM knock-out mice were also observed interacting with other mice, and were tested for their ability to “change the rules” in a classic test in animal learning called reversal learning. NrCAM knockout mice displayed impaired sociability, as indicated by avoidance of stranger mice. Although the NrCAM knockout mice were able to learn to find a hidden pedestal in a water maze task, they were impaired after the “rule change”—a sign of behavioral rigidity in these animals [6].

These results in an animal model provide evidence that NrCAM is involved in functions relevant to autism related behaviors. Because visual processing and thalamocortical deficits occur in ASDs [5-8], disruption of visual circuitry might contribute to ASD-related deficits such as eye gaze and interpretation of facial expressions, which influence social interactions.

References

1. Pinto, D., et al., Functional impact of global rare copy number variation in autism spectrum disorders.  Nature 466 (2010) 368-72.

2. Demyanenko GP, Riday TT, Tran TS, Dalal J, Darnell EP, Brennaman LH, Sakurai T, Grumet M, Philpot BD, Maness PF.   NrCAM deletion causes topographic mistargeting of thalamocortical axons to the visual cortex and disrupts visual acuity.  Journal of Neuroscience 26 (2011) 1545-1558.

3. Wu, S, et al. Association of Neuropilin-2 gene polymorphisms with autism in  Chinese Han population. Am J Med Genet B Neuropsychiatr. Genet. 144B (2007) 492-5.

4. Weiss LA, Arking DE; Gene Discovery Project of Johns Hopkins & the Autism Consortium, Daly MJ, Chakravarti A. A genome-wide linkage and association scan reveals novel loci for autism.  Nature 461(2009) 802-8.

5. Melin M, Carlsson B, Anckarsater H, Rastam M, Betancur C, Isaksson A, Gillberg C,  Dahl N.  Constitutional downregulation of Sema5A expression in autism. Neuropsychobiology. 54 (2006) 64-9.

6. Moy SS, Nonneman RJ, Young NB, Demyanenko GP, Maness PF. Impaired sociability and cognitive function in Nrcam-null mice. Behavioral Brain Research 205 (2009)123-31.


[1] A diversity of rare and common mutations appears to underlie abnormal brain development in autism spectrum disorders (ASDs). Large scale genetic studies have implicated genes encoding molecules that support synapse formation and function. For example, neural cell adhesion molecules (Neuroligins, Neurexins) and synaptic scaffold molecules (Shank family) have received much research attention in autism but others remain to be identified.  Neuron/Glia-related Cell Adhesion Molecule (NrCAM) is an axon guidance molecule encoded at human chromosomal locus 7q31. This region of chromosome 7 has been genetically linked to ASDs [reviewed in 1].


  1. April 5, 2011 at 1:30 pm

    Very interesting article! Thank you!

  2. April 5, 2011 at 2:25 pm

    great job. Please keep up the good work!

  3. Christina gutierrez
    April 5, 2011 at 7:26 pm

    Glad to see great breakthroughs in science are being made! Lets keep the research coming

  4. Dina
    April 5, 2011 at 7:34 pm

    Thanks,for help us with more information about the autism.

  5. April 6, 2011 at 12:28 am

    This is all well and good for understanding something more of how the brain functions when there are deficiencies. My studies have clearly shown that nutritional deficiencies are the basic cause for autism. Simple dietary changes can rid the children of the deficiencies causing autism and my research suggest a high degree of accuracy in predicting autism when several bio markers are known. We really do not need to know more of brain function but more as to cause!

    • Thomas Prendergast
      April 6, 2011 at 3:03 pm

      Mr. Rongey:
      Thanks for clarification to me regarding diet
      and autism. My 32 year old son has a basic
      chicken diet, he has always loved sweets, and
      sugar loaded foods. At meals he loads up on
      salt, and drinks cups of soft drinks. will not
      drink milk, loves milk shakes. I am at a loss
      how to get him on a better diet. He has never
      sat down and had a normal type meal. Is this
      a natural austic trait/
      Thanks

      Tommy

      • April 6, 2011 at 5:15 pm

        Tommy,
        The sixty plus nutrients identified to be low or lacking in those with autism are all found abundantly in the foods that contain cholesterol. My studies have consistently shown that when the missing nutrients are in the diet, the symptoms will more often than not disappear in a fairly short time.

  6. mandi
    April 6, 2011 at 4:54 am

    This is HUGE news I can not wait to hear and see more info regarding this study!

  7. Sue McGowan
    April 6, 2011 at 9:36 am

    Well, this is an interesting article, but I find the conclusion a bit backward, and a bit disturbing.

    First they gave mice a sensory impairment. Then they gave them some challenges. Then they concluded that mice with abnormal visual cortical responses displayed “a sign of behavioral rigidity” when they had to learn new rules to get through a maze!

    Isn’t it likely that the mice were confused by the same task with different rules and had a lot of trouble figuring it out, since they couldn’t see properly? The article doesn’t describe the impairment or say how much time the mice were given to figure out the new task – which makes me think the researchers didn’t consider these things much, if at all.

    Perhaps I’m the one jumping to conclusions here, by assuming that the mice were unable to adapt to new rules because of their visual impairment! (?) But I really find it strange that the concept “behavioral rigidity” would enter into the scientist’s minds at all – except that they’re drawing a comparison to autism where we always put so much focus on surface behaviour(s).

    I wonder if we shouldn’t make our extrapolation the other way – the mice are behaving in a rigid way because they don’t understand their environment, and they need help and extra time to understand a new environment. By extension, might people with autism who behave in a rigid way have some sensory impairment? We could, maybe, focus on their understanding of the environment instead of their rigid behaviour?

    Sue

    • Janice
      April 6, 2011 at 10:48 am

      I agree. When we focused on vision and hearing skills, and cleared the sinus cavity through medical intervention, the vision and hearing skills improved and developed.

      The DSM diagnosis for autism does not recognize issues concerning the senses or perception, when it should alert parent to seek vision and audio professionals for autistic behaviors. The ignorant perception by professionals is that autism is a only a social disorder….

      Children improve with meaningful therapy. Wouldn’t this would show that maybe the “NrCAM gene” is not deficient, but inhibited by inflammation and infection?

      It would help if the research focused on impairment of the senses instead of defining rigid behavior. To base everything on whether or not genes play a role is very limiting, especially since environment plays a bigger role in development of children.

      • Cindy
        April 6, 2011 at 2:00 pm

        I completly see your point and agree.

  8. Sarah
    April 6, 2011 at 2:18 pm

    Very cool. :)

  1. April 5, 2011 at 8:01 pm
  2. April 5, 2011 at 8:03 pm

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out / Change )

Twitter picture

You are commenting using your Twitter account. Log Out / Change )

Facebook photo

You are commenting using your Facebook account. Log Out / Change )

Google+ photo

You are commenting using your Google+ account. Log Out / Change )

Connecting to %s

%d bloggers like this: