Allostatic regulation of neuronal excitability by transient ischemia

During development and learning, a neuron actively maintains a stable state of excitability by adjusting the strength of its synaptic inputs (Turrigiano and Nelson, 2004). This homeostatic synaptic plasticity ensures that a neuron maintains a set-point spike firing rate when the overall synaptic input is increasing or decreasing (Turrigiano, 2008). Beside this homeostatic synaptic plasticity, neurons also reveal a homeostatic plasticity of neuronal intrinsic excitability by regulating voltage-dependent ion channels. When spontaneous activity is blocked for 2 days with tetrodotoxin (TTX), cortical neurons in primary cell culture increase their intrinsic excitability by a selective up-regulation of the voltage-dependent sodium current and a decrease of a voltage-dependent potassium current (Desai et al, 1999). This differential regulation of inward and outward currents increases intrinsic neuronal excitability and restores the neuron's set-point spike firing rate. A similar homeostatic stabilization of firing rates has been reported in embryonic motoneurons in vivo when spontaneous synaptic activity is reduced for 12 hours. Here, firing rates were restored by an increase in voltage-gated sodium current and a decrease in transient (I_A) and calcium-dependent potassium currents (Wilhelm et al, 2009).

In a series of elegant experiments and utilizing a wide spectrum of techniques, Deng et al (this issue) now demonstrate that neurons also show a homeostatic plasticity of intrinsic excitability when they are challenged by transient ischemia. Patch-clamp recordings from medium spiny and large aspiny (LA) neurons in adult rat striatal slices prepared 4 to 24 hours after induction of transient forebrain ischemia revealed an up-regulation of I_A in LA neurons, but not in medium spiny neurons. This cell type specific increase of I_A correlates with the higher resistance of LA neurons to ischemia (Pulsinelli et al, 1982). To identify the mechanism underlying the up-regulation of I_A in LA neurons, Deng et al performed neuropharmacological and immunohistochemical experiments and demonstrate that the α isoform of protein kinase C was selectively activated in LA neurons after ischemia.

The neuroprotective role of I_A was confirmed in primary neuronal cultures from striatum. In an in vitro ischemia model of combined oxygen/glucose deprivation I_Awas up-regulated in ischemia-resistant LA neurons, but not changed in medium spiny neurons. Recombinant expression of Kv1.2 or Kv4.2, which encode A-type potassium channels, caused a twofold increase in I_A associated with a decrease in neuronal excitability and cotransfection of Kv1.2 and Kv4.2 induced an increased resistance against oxygen/glucose deprivation ischemia. Deng et al provide further proof for a neuroprotective role of I_A by studying knockout mice lacking Kv1.2 and Kv4.2. Cultured cortical neurons from the ko mice showed a reduction in I_A amplitude and a higher sensitivity to oxygen/glucose deprivation ischemia.

In a last set of experiments Deng et al overexpressed the Kv4.2 subunit by infection with AAV1-Kv4.2 and could identify infected neurons by coinfection with AAV1-GFP. Thirteen days after transient forebrain ischemia, the neuronal viability of striatal neurons infected with AAV1-Kv4.2 plus AAV1-GFP was significantly increased as compared with striatal neurons in the contralateral side of the same animal infected with AAV1-GFP only.

The study by Deng et al is an excellent example for the allostatic regulation of neuronal excitability by a pathophysiological stimulus. The ischemia-induced up-regulation of I_A decreases neuronal excitability and contributes to the reestablishing of a homeostasis. The process of allostatic regulation may not end here, since rapidly inactivating A-type potassium channels may be converted into noninactivating delayed rectifiers by membrane lipids (Oliver et al, 2004).