Selective Alterations in Postsynaptic Markers of Chandelier Cell Inputs to Cortical Pyramidal Neurons in Subjects with Schizophrenia

• Published in: Neuropsychopharmacology (New York, N.Y.) Vol. 34; no. 9; pp. 2112 - 2124
• Main Authors: Cruz, Dianne A, Weaver, Cassandra L, Lovallo, Emily M, Melchitzky, Darlene S, Lewis, David A
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.08.2009; Nature Publishing Group
• Subjects: Adult; Adult and adolescent clinical studies; Aged; Animals; Ankyrins - metabolism; Antipsychotic Agents - pharmacology; Antipsychotics; Axons - metabolism; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Depressive Disorder, Major - metabolism; Female; Humans; Macaca; Macaca fascicularis; Male; Medical sciences; Medicine; Medicine & Public Health; Mental depression; Middle Aged; Nerve Tissue Proteins - metabolism; Neurons; Neuropharmacology; Neurosciences; original-article; Pharmacology. Drug treatments; Pharmacotherapy; Prefrontal Cortex - drug effects; Prefrontal Cortex - metabolism; Proteins; Psychiatry; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Psychopharmacology; Psychoses; Psychotropic drugs; Pyramidal Cells - metabolism; Schizophrenia; Schizophrenia - metabolism; Spectrin - metabolism; Synapses - metabolism; United States > US; Pittsburgh Pennsylvania; GABA; axon initial segment; ankyrin-G; IV spectrin; prefrontal cortex; Spectrin; Psychotropic; Central nervous system; Pharmacotherapy; Schizophrenia; Encephalon; Psychosis; Antipsychotic; Pyramidal neuron; Human; Drug; Pathophysiology; Treatment efficiency; Axon; Exploration; Prefrontal cortex; In vitro; Treatment; βIV spectrin; Neurotransmitter; Ankyrin; Neurotransmission
• ISSN: 0893-133X; 1740-634X; 1740-634X; 1470-634X
• DOI: 10.1038/npp.2009.36

Markers of GABA neurotransmission between chandelier neurons and their synaptic targets, the axon initial segment (AIS) of pyramidal neurons, are altered in the dorsolateral prefrontal cortex (dlPFC) of subjects with schizophrenia. For example, immunoreactivity for the GABA membrane transporter (GAT1) is decreased in presynaptic chandelier neuron axon terminals, whereas immunoreactivity for the GABA A receptor α 2 subunit is increased in postsynaptic AIS. To understand the nature and functional significance of these alterations, we determined the density, laminar distribution, and length of AIS immunoreactive (IR) for ankryin-G and β IV spectrin, two proteins involved in the regulation of synapse structure and ion channel clustering at AIS, in dlPFC area 46 from 14 matched triads of subjects with schizophrenia or major depressive disorder (MDD) and normal comparison participants. The density of ankyrin-G-IR AIS in the superficial, but not in the deep, cortical layers was significantly decreased by 15–19% in the subjects with schizophrenia relative to the other participant groups. In contrast, no group differences were present in the density of β IV spectrin-IR AIS. The length of labeled AIS did not differ across participant groups for either ankyrin-G or β IV spectrin. The density of ankyrin-G-IR AIS was not altered in the dlPFC of macaque monkeys chronically exposed to antipsychotic medications. Given the important role of ankyrin-G in the recruitment and stabilization of sodium channels and other integral membrane proteins to AIS, our findings suggest that these processes are selectively altered in superficial layer pyramidal neurons in subjects with schizophrenia.