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Carlos Portera-Cailliau, M.D., Ph.D.
Associate Professor of Neurology & Neurobiology
David Geffen School of Medicine
University of California, Los Angeles
Dana Foundation Grantee 2007-2009
Q: Your laboratory has discovered new insights about autism by studying the firing patterns of networks of neurons in a mouse model of Fragile X syndrome. Why have you taken this particular approach?
CARLOS PORTERA-CAILLIAU: We’re studying normal brain development because it will help us understand how diseases that affect this process might come about and how we might be able to treat them. Autism is a very general category of brain development disorders. Most cases of autism are sporadic, meaning we don’t know the cause. But, a minority of cases are genetic, and we’re learning a lot from the genes that cause autism, in part because we can make mouse models of specific diseases.
Fragile X syndrome is important because it is the most common inherited form of both autism and intellectual disability, what we used to call mental retardation. About a third of children with Fragile X will develop some autistic traits. So this approach allows us to first study the roles of this abnormal gene mutation in normal brain development and to make a mouse model of the disorder.
FMRP, the protein made by the gene that is defective in Fragile X, is very important for synapse function. Many molecular biologists have focused on the gene involved, and it’s taken a long time to learn about the function of FMRP. But this work hasn’t told us how the gene leads to a child who has abnormal socialization or intellectual dysfunction or other symptoms of autism. That’s because it’s harder to jump from a specific gene defect to behavioral symptoms than it is to jump from abnormal brain circuits to behavioral problems. If there is some dysfunction in the firing patterns of a network of neurons, particularly in a certain area of the brain, that might explain better how the children have trouble with language, learning, or interacting with peers. Studying circuits (independently of studying genetic aspects of this disease) may be an equally important avenue that so far has been relatively unexplored.
How might insights about network defects help find treatments for autism?
To treat the symptoms, we need to figure out what the problem is at the level of the network–how are neurons communicating poorly at the level of the entire circuit? Then maybe we could use drugs to treat the symptoms even if we can’t cure the underlying problem caused by the gene mutation. In many brain diseases, we’ve figured out the network problem, and then just tweaked neurotransmitters and neuron-to-neuron signals to treat the disabling symptoms.
For example, in epilepsy the main treatments are anticonvulsants, seizure medicines that suppress excessive neuronal firing. You can essentially make the seizures disappear or reduce them to a level that the individual can have a normal lifestyle. In Parkinson’s disease (PD), we add dopamine to brain circuits that are missing it. Alzheimer’s drugs increase levels of acetylcholine. Psychiatrists treat depression with drugs that raise levels of serotonin and norepinephrine.
Why not do the same in autism? We could figure out what the circuit problem is, whether too much activity or too little activity, and where that happens in the brain, and then, with medications or perhaps Deep Brain Stimulation, we could interfere with those circuits to bring them back to a normal level of activity. In the future, we might even be able to use optogenetics to stimulate or silence specific networks of neurons in particular brain areas with light as a way to treat abnormal symptoms. In my lab, we haven’t cared so much about the gene defect that causes the disease, or about the molecular signaling pathway that’s abnormal. Our feeling is that until a cure comes about from all the important molecular studies in autism, perhaps we can buy time by treating symptoms now through a better knowledge of the specific impairments in brain circuits. With epilepsy or PD, we’ve had remarkable success with this kind of approach.
You are using an imaging technique known as two-photon calcium imaging. How has this tool been useful for this problem?
Calcium imaging allows us to study both the firing of individual neurons, and large groups of neurons, hundreds at a time, without sticking electrodes into the brain. By looking at the activity of each individual neuron in this network, we can also determine how often one neuron fires when another neuron is firing, which tells us about the synchrony of the network. This can provide important information about how efficient the system is at performing computations or how likely it is to generate a seizure.
What have you found that’s unusual about the firing patterns of neurons in this mouse model of Fragile X?
First we looked at network activity in the brains of normal mice and found that right after birth and for the first two weeks of life, neurons in the neocortex of mice fire very synchronously. As many as 80 percent of cells fire together in bursts that last several seconds, followed by quiet periods of 30 seconds or more when there is no firing at all, then all the cells will fire again. This sort of up-and-down activity is very characteristic of early brain development. In fact, prior studies with EEG in healthy premature babies had suggested that large groups of neurons were firing synchronously, and these periods of firing were separated by periods of complete silence in the brain. So humans also undergo a period of time when all the neurons in the neocortex are firing together, but typically this happens in utero. In mice it happens after birth. We found that right around the end of the second post-natal week in normal mice, the activity becomes desynchronized and neurons start firing sparsely, or separately from one another. That is a very important transition period during brain maturation because you need the neurons to fire individually; otherwise it’s really difficult to encode information if all the cells fire at the same time.
A number of studies have suggested that brain maturation may not occur properly in autism. The evidence for this is quite strong in Fragile X syndrome. That made us think that perhaps the desynchronization of brain network activity is delayed or doesn’t happen at all in Fragile X mice, which would be another reflection of the immaturity of the brain. Lo and behold, that’s what we found. The activity of neurons in the cerebral cortex was about 20 percent more synchronous in the Fragile X mice than in the normal control mice. That synchrony came about because of elevated firing rates of the neurons. So the simple explanation for this higher synchrony is that all the neurons were firing more. If you fire more often, it’s more likely that sometimes you’ll fire when other cells are also firing.
How might synchronized firing of neurons explain the symptoms of autism?
It’s important for two reasons. First, it could explain the susceptibility to seizures in both the mouse model and in humans with Fragile X. Runaway synchrony of neuronal firing could lead to a seizure. Secondly, if all the neurons are firing synchronously, then you can’t encode as much information, which could interfere with learning. You need this desynchronization to learn normally. This transition around the second postnatal week in mice is a time when mice are starting to venture away from their mother, exploring the cage and becoming independent. It’s a critical age for mice, a period of rapid learning and rapid synapse formation. If something happens during such a critical period of brain maturation that could lead to autism, intellectual dysfunction, or other problems. For example, individuals with Fragile X show a hypersensitivity to sensory stimuli. It’s possible that excessive firing of neurons in response to tactile, auditory, or visual stimuli could explain the enhanced sensory responses experienced by affected individuals.
What does that suggest in terms of therapeutic approach?
In my view, if we really want to have an impact on the disease we have to intervene early. Symptoms in Fragile X are noticed early, before age 2. If the problem of brain wiring is one that happens in humans before birth (or even shortly after birth), it could have devastating consequences on learning, so how could we correct it in the adult?
I’m not saying that some of these network deficits can’t be reversed in the adult; in fact I would say that much of brain function in most children with autism is fairly normal, so it’s possible that tweaking the connectivity might restore a lot of the function to normal in older children or even adults. But in profoundly autistic individuals that approach may not work as well.
You found that this problem with synchrony and elevated firing rates in the Fragile X mice was much more pronounced when the mice were asleep or in a state of quiet wakefulness. What does that suggest?
This may explain the learning problems, because we know that sleep is critical to learning and consolidating memories. Also, it is during moments of quiet wakefulness, personal reflection, and introspection that we can really cogitate about important things we have to do, plan, or create. Imagine if your brain cells were firing three times more than normal or more synchronously during that time. It would probably interfere with your creativity and imagination, with encoding memories that you experienced earlier, or even with planning. This is still just a theory, but we think we’ve scratched on the surface of some incredibly important, fundamental brain defect at the level of circuits in autism–certainly in Fragile X mice, but possibly also in autism in general.