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The Journal of Neuroscience, May 27, 2009, 29(21):6982-6988; doi:10.1523/JNEUROSCI.0443-09.2009

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Development/Plasticity/Repair
Compensatory Enhancement of Intrinsic Spiking upon NKCC1 Disruption in Neonatal Hippocampus

Sampsa T. Sipilä,³ Kristiina Huttu,¹ Junko Yamada,¹ Ramil Afzalov,¹ Juha Voipio,¹ Peter Blaesse,¹ and Kai Kaila^1,2

¹Department of Biological and Environmental Sciences and ²Neuroscience Center, University of Helsinki, FI-00014 Helsinki, Finland, and ³Department of Clinical Neurophysiology, Oulu University Hospital, FI-90230 Oulu, Finland

Correspondence should be addressed to Prof. Kai Kaila, Department of Biological and Environmental Sciences, University of Helsinki, FI-00014 Helsinki, Finland. Email: kai.kaila{at}helsinki.fi

Depolarizing and excitatory GABA actions are thought to be important in cortical development. We show here that GABA has no excitatory action on CA3 pyramidal neurons in hippocampal slices from neonatal NKCC1^–/– mice that lack the Na–K–2Cl cotransporter isoform 1. Strikingly, NKCC1^–/– slices generated endogenous network events similar to giant depolarizing potentials (GDPs), but, unlike in wild-type slices, the GDPs were not facilitated by the GABA_A agonist isoguvacine or blocked by the NKCC1 inhibitor bumetanide. The developmental upregulation of the K–Cl cotransporter 2 (KCC2) was unperturbed, whereas the pharmacologically isolated glutamatergic network activity and the intrinsic excitability of CA3 pyramidal neurons were enhanced in the NKCC1^–/– hippocampus. Hence, developmental expression of KCC2, unsilencing of AMPA-type synapses, and early network events can take place in the absence of excitatory GABAergic signaling in the neonatal hippocampus. Furthermore, we show that genetic as well as pharmacologically induced loss of NKCC1-dependent excitatory actions of GABA results in a dramatic compensatory increase in the intrinsic excitability of glutamatergic neurons, pointing to powerful homeostatic regulation of neuronal activity in the developing hippocampal circuitry.

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Received Jan. 27, 2009; revised April 5, 2009; accepted April 23, 2009.

Correspondence should be addressed to Prof. Kai Kaila, Department of Biological and Environmental Sciences, University of Helsinki, FI-00014 Helsinki, Finland. Email: kai.kaila{at}helsinki.fi

Related articles in J. Neurosci.:

The Necessity of NKCC1: Loss of the Chloride Cotransporter in a Knock-Out Model and Potential Compensatory Mechanisms

Rebecca Wright
J. Neurosci. 2009 29: 13094-13096. [Full Text]  

This article has been cited by other articles:

				R. Wright The Necessity of NKCC1: Loss of the Chloride Cotransporter in a Knock-Out Model and Potential Compensatory Mechanisms J. Neurosci., October 21, 2009; 29(42): 13094 - 13096. [Full Text] [PDF]

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