Differential alterations of synaptic plasticity in dentate gyrus and CA1 hippocampal area of Calbindin-D28K knockout mice.

Regulation of the intracellular calcium concentration ([Ca(2+)](i)) is of critical importance for synaptic function. Therefore, neurons buffer [Ca(2+)](i) using intracellular Ca(2+)-binding proteins (CaBPs). Previous evidence suggests that Calbindin-D(28K) (CB), an abundantly expressed endogenous fast CaBP, plays an important role in neuronal survival, motor coordination, spatial learning paradigms and some forms of synaptic plasticity. In the present study, the role of CB in synaptic transmission and plasticity was further investigated using extracellular recordings of synaptic activity in cell- and dendritic layers of dentate gyrus (DG) and CA1 area in hippocampal slices from wild-type, heterozygous and homozygous CB knockout mice. The results demonstrate a consistent failure to maintain long-term potentiation (LTP) in hippocampal DG and CA1 area of knockout mice. Compared to wild-type mice, the paired-pulse ratio of EPSPs recorded in DG is significantly lower in slices from knockout mice, whereas it is significantly higher in CA1 area. The amplitude of the population spike recorded in CA1 area of wild-type mice steadily increases following tetanic stimulation, whereas it steadily decreases in knockout mice. The combined results demonstrate that the absence of CB results in an impairment of LTP maintenance in both hippocampal DG and CA1 area, whereas paired-pulse facilitation and cellular excitability in CA1 area are differentially affected. These results support the role of CB as a critical determinant for several forms of synaptic plasticity in hippocampal DG and CA1 area. It is hypothesized that CB functions as a postsynaptic Ca(2+) buffer as well as a presynaptic Ca(2+) sensor.

Overview of the clinical applications of vagus nerve stimulation.

Vagus nerve stimulation (VNS) has become an established therapy for difficult-to-treat epilepsy during the past 20 years. The vagus nerve provides a unique entrance to the brain. Electrical stimulation of this structure in the cervical region allows direct modulative access to subcortical brain areas, requiring only minimally invasive surgery with low risks involved. VNS therapy has shown to reduce epileptic seizures both in number and severity in a group of patients not responding to antiepileptic drugs. The effects are accompanied by an atypical set of central side effects. After the success of the VNS therapy with epilepsy, the technique has been applied to a wide variety of disorders, ranging from major depressive disorder to Alzheimer's disease. The results of several of these are promising. In this review, the results as well as the rationale for the different applications of VNS are discussed.

Dual role of calbindin-D28K in vesicular catecholamine release from mouse chromaffin cells.

Calbindin-D(28K) is suggested to play a postsynaptic role in neurotransmission and in the regulation of the intracellular Ca(2+) concentration. However, it is still unclear whether calbindin-D(28K) has a role in the regulation of exocytosis, either as Ca(2+) buffer or as Ca(2+) sensor. Amperometric recordings of catecholamine exocytosis from wild-type and calbindin-D(28K) knockout mouse chromaffin cells reveal a strong reduction in the number of released vesicles, as well as in the amount of neurotransmitter released per fusion event in knockout cells. However, Ca(2+) current recordings and Ca(2+) imaging experiments, including video-rate confocal laser scanning microscopy, revealed that the intracellular Ca(2+) dynamics are remarkably similar in wild-type and knockout cells. The combined results demonstrate that calbindin-D(28K) plays an important and dual role in exocytosis, affecting both release frequency and quantal size, apparently without strong effects on intracellular Ca(2+) dynamics. Consequently, the possibility that calbindin-D(28K) functions not only as a Ca(2+) buffer but also as a modulator of vesicular catecholamine release is discussed.

Kv1.1 channels of dorsal root ganglion neurons are inhibited by n-butyl-p-aminobenzoate, a promising anesthetic for the treatment of chronic pain.

In this study, we investigated the effects of the local anesthetic n-butyl-p-aminobenzoate (BAB) on the delayed rectifier potassium current of cultured dorsal root ganglion (DRG) neurons using the patch-clamp technique. The majority of the K(+) current of small DRG neurons rapidly activates and slowly inactivates at depolarized voltages. BAB inhibited the whole-cell K(+) current of these neurons with an IC(50) value of 228 microM. Dendrotoxin K (DTX(K)), a specific inhibitor of Kv1.1, reduced the DRG K(+) current at +20 mV by 34%, consistent with an important contribution of channels incorporating the Kv1.1 subunit to the delayed rectifier current. To further investigate the mechanism of BAB inhibition, we examined its effect on Kv1.1 channels heterologously expressed in mammalian tsA201 cells. BAB inhibits the Kv1.1 channels with an IC(50) value of 238 microM, similar to what was observed for the native DRG current. BAB accelerates the opening and closing of Kv1.1, but does not alter the midpoint of steady-state activation. BAB seems to inhibit Kv1.1 by stabilizing closed conformations of the channel. Coexpression with the Kv beta 1 subunit induces rapid inactivation and reduces the BAB sensitivity of Kv1.1. Comparison of the heterologously expressed Kv1.1 and native DRG currents indicates that the Kv beta 1 subunit does not modulate the gating of the DTX(K)-sensitive Kv1.1 channels of DRG neurons. Inhibition of the delayed rectifier current of these neurons may contribute to the long-duration anesthesia attained during the epidural administration of BAB.

Correlation between tissue depolarizations and damage in focal ischemic rat brain.

Ischemia-induced depolarizations may play a key role in the development of cerebral ischemic injury. Our goal was to assess the relationship between tissue depolarizations and tissue damage in focal ischemia. We performed multi-electrode cortical direct current (DC) potential recording and, subsequently, diffusion-weighted and T(2)-weighted magnetic resonance imaging (MRI) in rats after i) cortical application of KCl, and ii) permanent and transient middle cerebral artery (MCA)-occlusion in rats. Cortical KCl application induced 10.0+/-2.2 transient negative DC potential shifts per h on the ipsilateral hemisphere (i.e. cortical spreading depressions) (n=4). During 6 h of permanent MCA-occlusion (n=9) 1-10 DC potential shifts were observed, dependent on the brain location. Anoxic depolarization developed in the ischemic core. Outside ischemic areas DC potential shifts resembled cortical spreading depressions. Depolarizations in cortical ischemic borderzones were also transient, but generally long-lasting. Reperfusion induced 1 (n=5) or 3 h (n=6) after MCA-occlusion resulted in repolarization in 2.9+/-1.5 min. Ischemic lesion volumes after 7 h, calculated from diffusion-weighted and T(2)-weighted MR images, correlated significantly with total depolarization time in cortical perifocal zones (R=0.741, p<0.05), but not with the number of depolarizations. The extent of ischemic damage, as measured from alterations in the water diffusion coefficient and T(2), was also significantly related to the total time of depolarization (R=0.762 and 0.738, respectively, p<0.01). We conclude that early ischemic tissue injury is related to the total duration of tissue depolarization and not to the frequency of depolarizations.