Filters of the Mind

Despite more than a century of research on inhibitory neurons, very little is known about how this small population (10-20% of brain neurons) exerts its controlling effect on the brain.

Inhibitory neurons are pivotal for normal brain development, learning, and memory, so it is not surprising that they are involved in most neurological disorders. A recent Weizmann study, published in the January 2000 issue of Science, reveals key principles underlying the design and function of this inhibitory system.

By repressing the level of activity in neighboring neurons, inhibitory neurons (I-neurons) prevent the brain from quickly spinning out of control into hyperexcited states or full-blown epilepsy. One of the signs in children with autism and attention deficit hyperactivity disorder (ADHD) is I-neuron malfunction: their inhibitory system does not effectively suppress unwanted information, impeding their ability to make choices. I-neuron malfunction is involved in the majority of neurological disorders: Alzheimer's disease, neural trauma, addictions, and a wide range of psychiatric problems such as depression, obsessive-compulsive behavior, and schizophrenia.

In the past, researchers basically thought that I-neurons just spray an inhibitory neurotransmitter called GABA onto their neighbors. But this did not explain how they inhibit the right neurons at exactly the right time and to the right degree. The new study carried out in the laboratory of Prof. Henry Markram of the Neurobiology Department shows how this is achieved.

The research team found new types of I-neurons, revealing that this tiny population is much more diverse than previously thought. Further, using new methods that they developed, the researchers succeeded in recording directly how individual inhibitory neurons control their neighbors. They found that I-neurons build complex synapses (connections) onto their target neurons. The synapses selectively filter inhibitory messages, enabling I-neurons to shut down the activity in neighbors as required. These synapses act as fast-switching "if-then" filtering gates that allow inhibition to be applied only at the exact millisecond and only to the extent necessary.

Each I-neuron fixes complex if-then gates on thousands of neighboring neurons and is therefore "in charge" of controlling their activity. The gates allow I-neurons to rapidly switch their focus onto any neuron to which they are connected. This ingenious design principle is what enables the small group of I-neurons to exert such a sophisticated effect, simultaneously giving personal attention to the activity of each of the neurons to which they are linked.

The researchers showed that a "discussion" between I-neurons and target neurons is involved in deciding which type of if-then gate should be set up to filter the inhibitory message. This decision-making process could allow each neuron in the brain to be inhibited in a unique way. Dubbed the "interaction principle," this process generates maximal diversity of if-then gates, allowing more complex and more refined control over large numbers of neurons.

The researchers went on to reveal a remarkable ability of I-neurons: they can sense neurons that share the same functions in the brain. I-neurons "select" groups of target neurons to construct the same type of if-then gates, possibly enabling the I-neurons to control groups of neurons collectively. It also means that I-neurons can "sniff out" brain neurons that collaborate in the most elementary functions even if they seem different in almost every other way (i.e., they can identify neurons descended from the same "ancestors").

"I-neurons can trace the family trees of neurons. In other words, they could help us to work out how neurons are related to one another. This could one day enable us to map the functional aspect of the brain according to the genealogy of its neurons  an organizing principle we never dreamed would be possible, says Markram. The researchers believe that the ability to detect functionally related groups in the brain, called "the homogeneity principle," results from common signal molecules released by target cells. I-neurons may use the signal molecules to determine what kind of if-then gates to build. Future research designed to identify the nature of these molecules could yield a potent tool for mapping the functional structure of the brain.

Prof. Markram's research is supported by the Minna James Heineman Stiftung, Germany; the Abramson Family Foundation, North Bethesda, Maryland, and the Nella and Leon Benoziyo Center for Neurosciences.