John W. Olney, MD
John P Feighner Professor of Psychiatry, Professor of Pathology and Immunology
Areas of Research Interests
Our research focuses on the role of several neurotransmitter systems in a variety of neuropsychiatric disorders. Our early studies focused on glutamate (Glu) and simple excitotoxicity (excessive activation of Glu receptors), as a mechanism that triggers neurodegeneration in acute brain injury conditions such as stroke, head trauma and epilepsy.
More recently we have expanded our focus to include complex excitotoxicity, a newly discovered phenomenon whereby blockade of Glu receptors on inhibitory neurons causes disinhibition of excitatory pathways leading to pathological release of excitotoxic activity from both cholinergic and glutamatergic neurons. We are examining the potential role of complex excitotoxicity in chronic neuropsychiatric disorders, such as schizophrenia and Alzheimers disease.
Most recently we have directed increased attention to developmental mechanisms of neurodegeneration. We have discovered that during synaptogenesis there are several mechanisms by which massive neurodegeneration can be induced in the developing brain. For example, excessive activation of Glu receptors triggers excitotoxic neurodegeneration, and insufficient activation of NMDA Glu receptors or excessive activation of GABAA receptors triggers widespread apoptotic neurodegeneration. Recently we reported (5) that ethanol, which has both NMDA receptor blocking and GABAA receptor activation properties, triggers widespread apoptotic neurodegeneration throughout the developing forebrain during synaptogenesis. This provides an explanation for the reduced brain mass and lifelong neurobehavioral disturbances associated with the human fetal alcohol syndrome and identifies a type of mechanism that may be operative in other developmental neuropathology syndromes as well.
Olney JW: Excitatory amino acids and neuropsychiatric disorders. Biol Psychiatry 1989; 26:505-525.
Olney JW, Labruyere J, Wang G, Wozniak DF, Price MT Sesma MA: NMDA antagonist neurotoxicity: Mechanism and prevention. Science 1991; 254:1515-1518.
Olney JW and Farber NB: Glutamate receptor dysfunction and schizophrenia. Arch Gen Psychiatry 52; 998-1007.
Ikonomidou C, Ishimaru MJ, Wozniak DF, Koch C, Bittigau P, Price MT, Stefovska V, Hrster F, Tenkova T, Dikranian K, Olney JW: Ethanol-induced apoptotic neurodegeneration and the fetal alcohol syndrome. Science 2000; 287:1056-1060.
Funded Research Projects
NICHD(PI):Acute Brain Injury, Mechanisms and Consequences
NIDA(PI):Developmental Brain Damage by Drugs of Abuse
NIEHS(Key Personnel):Neurodevelopmental Apoptosis
NICHD(PI):Anesthesia-Induced Developmental Neuroapoptosis in non-Human Primates