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The Journal of Neuroscience, January 3, 2007, 27(1):59-68; doi:10.1523/JNEUROSCI.4502-06.2007

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Neurobiology of Disease
Hyperexcitability of Distal Dendrites in Hippocampal Pyramidal Cells after Chronic Partial Deafferentation

Xiang Cai,^1 * Dong-Sheng Wei,^2 * Sandra E. Gallagher,^1,3 Ashish Bagal,^1,4 Yan-Ai Mei,⁵ Joseph P. Y. Kao,^1,6 Scott M. Thompson,¹ and Cha-Min Tang^1,2,7

Departments of ¹Physiology, ²Neurology, and ³Medical and Research Technology and ⁴MD/PhD Training Program, University of Maryland School of Medicine, Baltimore, Maryland 21201, ⁵Department of Physiology and Biophysics, School of Life Sciences, Fudan University, Shanghai 200433, China, ⁶Medical Biotechnology Center, University of Maryland Biotechnology Institute, Baltimore, Maryland 21201, and ⁷Neurology Service, Baltimore Veterans Affairs Medical Center, Baltimore, Maryland 21201

Correspondence should be addressed to Scott Thompson, Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201. Email: sthom003{at}umaryland.edu

Traumatic injury to the CNS results in chronic partial deafferentation of subsets of surviving neurons. Such injuries are often followed by a delayed but long-lasting period of aberrant hyperexcitability. The cellular mechanisms underlying this delayed hyperexcitability are poorly understood. We developed an in vitro model of deafferentation and reactive hyperexcitability using organotypic hippocampal slice cultures to study the underlying cellular mechanisms. One week after transection of the Schaffer collateral and temporoammonic afferents to CA1 neurons, brief tetanic stimulation of the residual excitatory synapses produced abnormally prolonged depolarizations, compared with responses in normally innervated neurons. Responses to weak stimulation, in contrast, were unaffected after deafferentation. Direct stimulation of distal apical dendrites using focal photolysis of caged glutamate triggered abnormally prolonged plateau potentials in the deafferented neurons when strong stimulation was given, but responses to weak stimulation were not different from controls. An identical phenotype was produced by chronic "chemical deafferentation" with glutamate receptor antagonists. Responses to strong synaptic and photolytic stimulation were selectively prolonged by small-conductance (SK-type) calcium-activated potassium channel blockers in normally innervated cells but not after deafferentation. No significant changes in SK2 mRNA or protein levels, GABAergic inhibition, glutamate receptor function, input resistance, or action potential parameters were observed after chronic deafferentation. We suggest that a posttranslational downregulation of SK channel function in thin distal dendrites is a significant contributor to deafferentation-induced reactive hyperexcitability.

Key words: epilepsy; glutamate; potassium channels; injury; synaptic plasticity; deafferentation

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Received Jan. 25, 2006; revised Nov. 10, 2006; accepted Nov. 12, 2006.

Correspondence should be addressed to Scott Thompson, Department of Physiology, University of Maryland School of Medicine, 655 West Baltimore Street, Baltimore, MD 21201. Email: sthom003{at}umaryland.edu

This article has been cited by other articles:

				M. Shin and D. M. Chetkovich Activity-dependent Regulation of h Channel Distribution in Hippocampal CA1 Pyramidal Neurons J. Biol. Chem., November 9, 2007; 282(45): 33168 - 33180. [Abstract] [Full Text] [PDF]

				R. E. Hoffman A Social Deafferentation Hypothesis for Induction of Active Schizophrenia Schizophr Bull, September 1, 2007; 33(5): 1066 - 1070. [Abstract] [Full Text] [PDF]

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