TY - JOUR
T1 - Selective Alterations in Postsynaptic Markers of Chandelier Cell Inputs to Cortical Pyramidal Neurons in Subjects with Schizophrenia
AU - Cruz, Dianne A.
AU - Weaver, Cassandra L.
AU - Lovallo, Emily M.
AU - Melchitzky, Darlene S.
AU - Lewis, David A.
N1 - Funding Information:
Supported by NIH grants MH043784, MH045156, and MH084053 from the National Institute of Mental Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Mental Health or the National Institutes of Health. The authors thank Dr Matthew Rasband for providing the bIV spectrin antibody, Mary Brady for excellent assistance with the figures, Lindsay Karr for preparing the manuscript, and the members of the Clinical Services and Diagnostics Core of the Conte Center for the Neuroscience of Mental Disorders (MH084053) for their assistance in diagnostic assessments.
PY - 2009/8
Y1 - 2009/8
N2 - 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 α2 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 ΒIV 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 ΒIV spectrin-IR AIS. The length of labeled AIS did not differ across participant groups for either ankyrin-G or ΒIV 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.
AB - 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 α2 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 ΒIV 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 ΒIV spectrin-IR AIS. The length of labeled AIS did not differ across participant groups for either ankyrin-G or ΒIV 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.
KW - Ankyrin-G
KW - Axon initial segment
KW - GABA
KW - Prefrontal cortex
KW - βIV spectrin
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U2 - 10.1038/npp.2009.36
DO - 10.1038/npp.2009.36
M3 - Article
C2 - 19322171
AN - SCOPUS:67651113930
VL - 34
SP - 2112
EP - 2124
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
SN - 0893-133X
IS - 9
ER -