1. ¹Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, USA
2. ²Neuroscience, University of Pittsburgh, Pittsburgh, PA, USA
3. ³Department of Biology, Mercyhurst College, Erie, PA, USA

Correspondence: Dr DA Lewis, Department of Psychiatry, University of Pittsburgh, 3811 O'Hara Street, W1651 BST, Pittsburgh, PA 15213, USA. Tel: +1412 624 3934, Fax: +1412 624 9910, E-mail: lewisda@upmc.edu

⁴Current address: Department of Psychiatry, University of Texas Health Science Center at San Antonio

Received 18 December 2008; Revised 11 February 2009; Accepted 12 February 2009; Published online 25 March 2009.

Abstract

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 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 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 IV spectrin-IR AIS. The length of labeled AIS did not differ across participant groups for either ankyrin-G or 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.