Altered GABA neurotransmission and prefrontal cortical dysfunction in schizophrenia.
Dysfunction of the dorsolateral prefrontal cortex appears to be a central feature of the pathophysiology of schizophrenia, and this dysfunction may be related to alterations in gamma aminobutyric acid (GABA) neurotransmission. Determining the causes and consequences of altered GABA neurotransmission in schizophrenia, and the relationship of these changes to other abnormalities in prefrontal cortical circuitry, requires an understanding of which of the multiple subpopulations of cortical GABA neurons are affected. The chandelier class of GABA neurons, especially those located in the middle layers of the prefrontal cortex (PFC), have been hypothesized to be preferentially involved in schizophrenia because they 1) receive direct synaptic input from dopamine axons, 2) exert powerful inhibitory control over the excitatory output of layer 3 pyramidal neurons, and 3) undergo substantial developmental changes during late adolescence, the typical age of onset of schizophrenia. Consistent with this hypothesis, the axon terminals of chandelier neurons, as revealed by immunoreactivity for the GABA membrane transporter, are reduced substantially in the middle layers of the PFC in schizophrenic subjects. This alteration appears to be selective for the chandelier class of GABA neurons and for the disease process of schizophrenia. These findings provide insight into the pathophysiologic mechanisms underlying prefrontal cortical dysfunction in schizophrenia, and they reveal new targets for therapeutic intervention in this illness.
Lewis
D A
DA
Department of Psychiatry, University of Pittsburgh, Pennsylvania 15213, USA.
Pierri
J N
JN
Volk
D W
DW
Melchitzky
D S
DS
Woo
T U
TU
D000293:Adolescent; D000818:Animals; D001369:Axons / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D006801:Humans; D007223:Infant; D008568:Memory / Q000502:physiology; D009474:Neurons / Q000502:physiology; D017397:Prefrontal Cortex / Q000378:metabolism* / Q000503:physiopathology*; D012559:Schizophrenia / Q000378:metabolism* / Q000503:physiopathology*; D009435:Synaptic Transmission / Q000502:physiology*; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D005680:gamma-Aminobutyric Acid