Belmont--January 2004, Harvard Medical School affiliate McLean Hospital--McLean Hospital researchers have made a discovery that could help explain one of the most powerful paradigms in modern psychology, Pavlovian fear conditioning. Alterations in fear conditioning are thought to play a role in such common psychiatric illnesses as post-traumatic stress disorder, generalized anxiety disorder and panic disorder. The discovery by Vadim Bolshakov, PhD, and his colleagues, reported in the Jan. 8 Neuron, could lead to a better understanding of these debilitating illnesses.

     As readers of introductory psychology texts know, animals easily learn to fear a harmless stimulus, such as a tone, if that stimulus is paired with a painful one, such as a foot shock. For this fear conditioning to take root in the brain, neurons located in the almond-shaped amygdala must become extraordinarily sensitized to the tone-carrying stimulus-so sensitive that they will continue to fire even in the absence of an auditory stimulus. Yet each neuron in the amygdala is capable of receiving many, even thousands, of inputs.  How are neurons able to exhibit such sensitivity, known as long-term potentiation (LTP), to a single input amid such a plethora of signals?

     The answer, it appears, is by cleaning up their synapses. For LTP to occur, a presynaptic neuron must release the chemical glutamate in a continuous manner. Normally, glutamate is removed from the synaptic cleft by housekeeping proteins, known as glutamate transporters, in the postsynaptic neuron. Suspecting that this glutamate-removal system might play a role in maintaining input specificity, Bolshakov, director of McLean Hospital's Cellular Neurobiology Laboratory, and his colleagues blocked the glutamate transporter in neurons of the amygdala. They then monitored the cells' ability to differentiate between LTP-inducing signals from two auditory inputs, one from the thalamus and the other from the cortex. The cells' ability to distinguish between inputs was lost. The cells became sensitized to both inputs, even though LTP had only been induced in one.

     Bolshakov and his colleagues believe that spillover of excess glutamate may be responsible. "We found that if the glutamate transporter is not functioning efficiently, glutamate escapes from the stimulated synapse and activates the unstimulated one."

     The experiments, conducted in rodent amygdala neurons, could have relevance for humans. "We know that the amygdala is involved in emotional learning in humans," said Bolshakov. "Post-traumatic stress disorder is a form of amygdala-based learning. A person comes to associate insignificant biological stimuli with painful memories."

     Although it is not clear whether glutamate transporters play a role in post-traumatic stress disorder, glutamate release and uptake is thought to be impaired in a variety of psychiatric illnesses, from Alzheimer's disease to schizophrenia.

     "Glutamate uptake mechanisms are regulated by different molecules. They could be down-regulated under different pathological conditions," said Bolshakov. "It would be important to investigate in detail such regulatory pathways using different neurobiological and genetic approaches."