Smoking and schizophrenia: abnormal nicotinic receptor expression.

Area of Science:

• Neuroscience
• Genetics
• Psychiatry

Background:

• Neuronal nicotinic receptors play a role in schizophrenia neuropathophysiology.
• Nicotine administration can normalize auditory evoked potential deficits in schizophrenia patients.
• Reduced levels of high and low affinity nicotinic receptors are observed in postmortem brains of schizophrenic individuals.

Purpose of the Study:

• To investigate the role of neuronal nicotinic receptors, specifically the alpha-7 gene, in the neuropathophysiology of schizophrenia.
• To examine the expression and genetic structure of the human alpha-7 nicotinic receptor gene in schizophrenia.

Main Methods:

• Analysis of auditory evoked potentials in response to nicotine.
• Postmortem brain tissue analysis to quantify nicotinic receptor levels.
• Genetic linkage studies to assess the chromosomal locus of the alpha-7 gene.
• Gene cloning and expression analysis of the human alpha-7 gene, including investigation of duplications.
• Administration of alpha-7 receptor antagonists to rodents to study gating deficits.

Main Results:

• Nicotine normalized auditory evoked potential deficits in schizophrenia subjects.
• Nicotinic receptors were decreased in the postmortem brains of schizophrenics.
• The human alpha-7 nicotinic receptor gene locus (15q14) showed linkage to gating deficits.
• Alpha-7 receptor antagonists induced gating deficits in rodents.
• A partial duplication of the human alpha-7 gene was identified, expressed in normal subjects but absent in some schizophrenic patients.

Conclusions:

• Abnormal expression and function of the neuronal nicotinic receptor gene family are suggested in schizophrenia.
• The alpha-7 nicotinic receptor and its gene appear to be critically involved in schizophrenia.
• Genetic alterations, such as gene duplication, may contribute to schizophrenia pathogenesis.