Cerebral Cortex, Vol. 12, No. 10, 1063-1070,
October 2002
© 2002 Oxford University Press
Reciprocal Alterations in Pre- and Postsynaptic Inhibitory Markers at Chandelier Cell Inputs to Pyramidal Neurons in Schizophrenia
1 Departments of Neuroscience, , 2 Psychiatry and , 3 Statistics, University of Pittsburgh, PA 15260, USA and , 4 Institute of Pharmacology, University of Zurich, CH-8057 Zurich, Switzerland
David A. Lewis, University of Pittsburgh, 3811 O’Hara Street, W1650 BST, Pittsburgh, PA 15213, USA. Email: lewisda{at}msx.upmc.edu.
In the prefrontal cortex of subjects with schizophrenia, markers of the synthesis and re-uptake of GABA appear to be selectively altered in a subset of interneurons that includes chandelier cells. Determining the effect of these disturbances in presynaptic GABA markers on inhibitory signaling requires knowledge of the status of GABAA receptors at the postsynaptic targets of chandelier cells, the axon initial segments (AIS) of pyramidal neurons. Because the 
2 subunit of the GABAA receptor is preferentially localized at pyramidal neuron AIS, we quantified 2 subunit immunoreactive AIS in tissue sections containing prefrontal cortex area 46 from 14 matched triads of subjects with schizophrenia, subjects with major depression and control subjects. Systematic, random sampling revealed that the mean number of 2-labeled AIS per mm2 in subjects with schizophrenia was significantly (P = 0.007) increased by 113% compared to control subjects and non-significantly increased compared to subjects with major depression. Furthermore, within subjects with schizophrenia, the density of 2-labeled AIS was negatively correlated (r = –0.49, P = 0.038) with the density of chandelier axon terminals immunoreactive for the GABA membrane transporter. These data suggest that GABAA receptors are up-regulated at pyramidal neuron AIS in response to deficient GABA neuro-transmission at chandelier axon terminals in schizophrenia. Thus, disturbances in inhibition at the chandelier neuron–pyramidal neuron synapse may be a critical component of prefrontal cortical dysfunction in schizophrenia.
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  W. M. Bullock, K. Cardon, J. Bustillo, R. C. Roberts, and N. I. Perrone-Bizzozero Altered Expression of Genes Involved in GABAergic Transmission and Neuromodulation of Granule Cell Activity in the Cerebellum of Schizophrenia Patients Am J Psychiatry, December 1, 2008; 165(12): 1594 - 1603. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Lewis, R. Y. Cho, C. S. Carter, K. Eklund, S. Forster, M. A. Kelly, and D. Montrose Subunit-Selective Modulation of GABA Type A Receptor Neurotransmission and Cognition in Schizophrenia Am J Psychiatry, December 1, 2008; 165(12): 1585 - 1593. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Gonzalez-Burgos and D. A. Lewis GABA Neurons and the Mechanisms of Network Oscillations: Implications for Understanding Cortical Dysfunction in Schizophrenia Schizophr Bull, September 1, 2008; 34(5): 944 - 961. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. M. Morris, T. Hashimoto, and D. A. Lewis Alterations in Somatostatin mRNA Expression in the Dorsolateral Prefrontal Cortex of Subjects with Schizophrenia or Schizoaffective Disorder Cereb Cortex, July 1, 2008; 18(7): 1575 - 1587. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Menzies, C. Ooi, S. Kamath, J. Suckling, P. McKenna, P. Fletcher, E. Bullmore, and C. Stephenson Effects of {gamma}-Aminobutyric Acid-Modulating Drugs on Working Memory and Brain Function in Patients With Schizophrenia Arch Gen Psychiatry, February 1, 2007; 64(2): 156 - 167. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Loup, F. Picard, V. M. Andre, P. Kehrli, Y. Yonekawa, H.-G. Wieser, and J.-M. Fritschy Altered expression of {alpha}3-containing GABAA receptors in the neocortex of patients with focal epilepsy Brain, December 1, 2006; 129(12): 3277 - 3289. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. A. Lewis and B. Moghaddam Cognitive Dysfunction in Schizophrenia: Convergence of {gamma}-Aminobutyric Acid and Glutamate Alterations. Arch Neurol, October 1, 2006; 63(10): 1372 - 1376. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Pillai-Nair, A. K. Panicker, R. M. Rodriguiz, K. L. Gilmore, G. P. Demyanenko, J. Z. Huang, W. C. Wetsel, and P. F. Maness Neural Cell Adhesion Molecule-Secreting Transgenic Mice Display Abnormalities in GABAergic Interneurons and Alterations in Behavior J. Neurosci., May 4, 2005; 25(18): 4659 - 4671. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. M. Spencer, P. G. Nestor, R. Perlmutter, M. A. Niznikiewicz, M. C. Klump, M. Frumin, M. E. Shenton, and R. W. McCarley Neural synchrony indexes disordered perception and cognition in schizophrenia PNAS, December 7, 2004; 101(49): 17288 - 17293. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Meier and R. Grantyn Preferential accumulation of GABAA receptor {gamma}2L, not {gamma}2S, cytoplasmic loops at rat spinal cord inhibitory synapses J. Physiol., September 1, 2004; 559(2): 355 - 365. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. A. Cruz, S. M. Eggan, E. C. Azmitia, and D. A. Lewis Serotonin1A Receptors at the Axon Initial Segment of Prefrontal Pyramidal Neurons in Schizophrenia Am J Psychiatry, April 1, 2004; 161(4): 739 - 742. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Jablonska, A. L. Smith, S. L. Palmer, S. C. Noctor, and S. L. Juliano GABAA Receptors Reorganize when Layer 4 in Ferret Somatosensory Cortex is Disrupted by Methylazoxymethanol (MAM) Cereb Cortex, April 1, 2004; 14(4): 432 - 440. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Spencer, P. G. Nestor, M. A. Niznikiewicz, D. F. Salisbury, M. E. Shenton, and R. W. McCarley Abnormal Neural Synchrony in Schizophrenia J. Neurosci., August 13, 2003; 23(19): 7407 - 7411. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Q. Xu, E. de la Cruz, and S. A. Anderson Cortical Interneuron Fate Determination: Diverse Sources for Distinct Subtypes? Cereb Cortex, June 1, 2003; 13(6): 670 - 676. [Abstract] [Full Text] [PDF]
|
|