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The Journal of Neuroscience, January 12, 2005, 25(2):372-383; doi:10.1523/JNEUROSCI.4035-04.2005

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Neurobiology of Disease
Relationship of Brain-Derived Neurotrophic Factor and Its Receptor TrkB to Altered Inhibitory Prefrontal Circuitry in Schizophrenia

Takanori Hashimoto,¹ Sarah E. Bergen,² Quyen L. Nguyen,² Baoji Xu,⁴ Lisa M. Monteggia,⁵ Joseph N. Pierri,¹ Zhuoxin Sun,³ Allan R. Sampson,³ and David A. Lewis^1,2

Departments of ¹Psychiatry, ²Neuroscience, and ³Statistics, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, ⁴Department of Pharmacology, Georgetown University Medical School, Washington, DC 20057, and ⁵Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Dysfunction of inhibitory neurons in the prefrontal cortex (PFC), represented by decreased expression of GABA-related genes such as the 67 kDa isoform of glutamate decarboxylase (GAD₆₇) and parvalbumin (PV), appears to contribute to cognitive deficits in subjects with schizophrenia. We investigated the involvement of signaling mediated by brain-derived neurotrophic factor (BDNF) and its receptor tyrosine kinase TrkB in producing the altered GABA-related gene expression in schizophrenia. In 15 pairs of subjects with schizophrenia and matched control subjects, both BDNF and TrkB mRNA levels, as assessed by in situ hybridization, were significantly decreased in the PFC of the subjects with schizophrenia, whereas the levels of mRNA encoding the receptor tyrosine kinase for neurotrophin-3, TrkC, were unchanged. In this cohort, within-pair changes in TrkB mRNA levels were significantly correlated with those in both GAD₆₇ and PV mRNA levels. Decreased BDNF, TrkB, and GAD₆₇ mRNA levels were replicated in a second cohort of 12 subject pairs. In the combined cohorts, the correlation between within-pair changes in TrkB and GAD₆₇ mRNA levels was significantly stronger than the correlation between the changes in BDNF and GAD₆₇ mRNA levels. Neither BDNF nor TrkB mRNA levels were changed in the PFC of monkeys after a long-term exposure to haloperidol. Genetically introduced decreases in TrkB expression, but not in BDNF expression, also resulted in decreased GAD₆₇ and PV mRNA levels in the PFC of adult mice; in addition, the cellular pattern of altered GAD₆₇ mRNA expression paralleled that present in schizophrenia. Decreased TrkB signaling appears to underlie the dysfunction of inhibitory neurons in the PFC of subjects with schizophrenia.

Key words: cortex; GABA; GAD; in situ hybridization; parvalbumin; postmortem; trkB hypomorphic

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Received June 8, 2004; revised November 18, 2004; accepted November 18, 2004.

This article has been cited by other articles:

				J. G. Maldonado-Aviles, A. A. Curley, T. Hashimoto, A. L. Morrow, A. J. Ramsey, P. O'Donnell, D. W. Volk, and D. A. Lewis Altered Markers of Tonic Inhibition in the Dorsolateral Prefrontal Cortex of Subjects With Schizophrenia Am J Psychiatry, April 1, 2009; 166(4): 450 - 459. [Abstract] [Full Text] [PDF]

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				K. Y. Tseng, B. L. Lewis, T. Hashimoto, S. R. Sesack, M. Kloc, D. A. Lewis, and P. O'Donnell A Neonatal Ventral Hippocampal Lesion Causes Functional Deficits in Adult Prefrontal Cortical Interneurons J. Neurosci., November 26, 2008; 28(48): 12691 - 12699. [Abstract] [Full Text] [PDF]

				N. Mellios, H.-S. Huang, A. Grigorenko, E. Rogaev, and S. Akbarian A set of differentially expressed miRNAs, including miR-30a-5p, act as post-transcriptional inhibitors of BDNF in prefrontal cortex Hum. Mol. Genet., October 1, 2008; 17(19): 3030 - 3042. [Abstract] [Full Text] [PDF]

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				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]

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				N. H. Woo and B. Lu Regulation of Cortical Interneurons by Neurotrophins: From Development to Cognitive Disorders Neuroscientist, February 1, 2006; 12(1): 43 - 56. [Abstract] [PDF]

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