Lorna W. Role, Ph.D.
Professor and Chair
Department of Neurobiology and Behavior
and Center for Nervous System Disorders
State University of New York, Stony Brook

Neuregulin – Signaling and Nicotinic Receptor Modulation of Cortico-Limbic Circuits

Along with the brain chemical glutamate, cholinergic neurotransmission has been extensively implicated in cognitive dysfunction and disease and is the topic of interest for Dr. Lorna Role. The Role lab studies a particular signaling network that maintains and promotes healthy cholinergic cells in the brain. When these signaling cascades break down, cognitive problems result, often presenting in the form of schizophrenia. Dr. Role’s work is a prime example of how very small changes in protein signaling can cause very severe and widespread changes in behavior.

In the words of Dr. Role, “It all started with a molecularly-brave graduate student in the lab seeking to identify the ‘factor’ that regulated the expression of nicotine-gated channels (or nAChRs). She cloned and identified this molecule from a chick spinal cord library in 1993. In 1998, she published her thesis on the neuronal Acetylcholine Receptor Inducing Activity or ‘nARIA’ in Neuron. The thesis included the sequence of what turned out to be an enormous gene, comparing it, as is traditional, with its mouse and human relatives, and demonstrating its activity as a regulator of nAChR expression.” Little did she or Dr. Role know at the time that nARIA would turn out to be a splice isoform of Neuregulin 1, which has since been identified as a schizophrenia susceptibility gene implicated in cholinergic signaling.

Central cholinergic systems have been strongly implicated in a number of neuropsychiatric diseases including attentional disorders, schizophrenia, depression and Alzheimer’s dementia. These cholinergic systems are believed to provide important modulatory control of synaptic excitability. The Role laboratory studies the generation, plasticity and maintenance of cholinergic and cholinoceptive synapses in the mammalian brain. Recent work from this research group has shown that novel classes of signaling molecules, which are products of the neuregulin-1 gene, are important in the susceptibility to such diseases.

Neuregulin-1-signaling is essential to the maintenance of normal cholinergic circuits, which is accomplished through regulation of the expression of a family of acetycholine receptors (nAchR) in the brain. These receptors interact with a number of signaling cascades involved in cell survival, thus keeping cholinergic neurotransmission networks intact. In collaboration with Dr. David Talmage, the Role lab has incorporated behavioral, electrophysiological and genetic techniques to probe changes in cortico-limbic circuitry that result from aberrations in Neuregulin1 and nAChR expression. These studies have led to many striking discoveries and have suggested that many of the cholinergic cells expressing these genes are part of CNS circuits and synapses related to disease, with a particular emphasis on the neuronal circuits underlying the pathological symptoms of schizophrenia.