A Ca(2+) threshold for induction of spike-timing-dependent depression in the mouse striatum.

The striatum is the principal input nucleus of the basal ganglia, receiving glutamatergic afferents from the cerebral cortex. There is much interest in mechanisms of synaptic plasticity in the corticostriatal synapses. We used two-photon microscopy and whole-cell recording to measure changes in intracellular calcium concentration ([Ca(2+)](i)) associated with spike-time-dependent plasticity in mouse striatum. Uncaging glutamate adjacent to a dendritic spine caused a postsynaptic potential at the soma and a rise in spine [Ca(2+)](i). Action potentials elicited at the soma raised both dendrite and spine [Ca(2+)](i). Pairing protocols in which glutamate uncaging preceded action potentials by 10 ms (pre-post protocol) produced supralinear increases in spine [Ca(2+)](i) compared with the sum of increases seen with uncaging and action potentials alone, or timing protocols in which the uncaging followed the action potentials (post-pre protocols). The supralinear component of the increases in [Ca(2+)](i) were eliminated by the voltage-sensitive calcium channel blocker nimodipine. In the adjacent parent dendrites, the increases in [Ca(2+)](i) were neither supralinear nor sensitive to the relative pre-post timing. In parallel experiments, we investigated the effects of these pairing protocols on spike-timing-dependent synaptic plasticity. Long-term depression (t-LTD) of corticostriatal inputs was induced by pre-post but not post-pre protocols. Intracellular calcium chelators and calcium antagonists blocked pre-post t-LTD, confirming that elevated calcium entering via voltage-sensitive calcium channels is necessary for t-LTD. These findings confirm a spine [Ca(2+)](i) threshold for induction of t-LTD in the corticostriatal pathway, mediated by the supralinear increase in [Ca(2+)](i) associated with pre-post induction protocols.

Reverse of age-dependent memory impairment and mitochondrial DNA damage in microglia by an overexpression of human mitochondrial transcription factor a in mice.

Mitochondrial DNA (mtDNA) is highly susceptible to injury induced by reactive oxygen species (ROS). During aging, mutations of mtDNA accumulate to induce dysfunction of the respiratory chain, resulting in the enhanced ROS production. Therefore, age-dependent memory impairment may result from oxidative stress derived from the respiratory chain. Mitochondrial transcription factor A (TFAM) is now known to have roles not only in the replication of mtDNA but also its maintenance. We herein report that an overexpression of TFAM in HeLa cells significantly inhibited rotenone-induced mitochondrial ROS generation and the subsequent NF-kappaB (nuclear factor-kappaB) nuclear translocation. Furthermore, TFAM transgenic (TG) mice exhibited a prominent amelioration of an age-dependent accumulation of lipid peroxidation products and a decline in the activities of complexes I and IV in the brain. In the aged TG mice, deficits of the motor learning memory, the working memory, and the hippocampal long-term potentiation (LTP) were also significantly improved. The expression level of interleukin-1beta (IL-1beta) and mtDNA damages, which were predominantly found in microglia, significantly decreased in the aged TG mice. The IL-1beta amount markedly increased in the brain of the TG mice after treatment with lipopolysaccharide (LPS), whereas its mean amount was significantly lower than that of the LPS-treated aged wild-type mice. At the same time, an increased mtDNA damage in microglia and an impaired hippocampal LTP were also observed in the LPS-treated aged TG mice. Together, an overexpression of TFAM is therefore considered to ameliorate age-dependent impairment of the brain functions through the prevention of oxidative stress and mitochondrial dysfunctions in microglia.

Active propagation of dendritic electrical signals in C. elegans.

Active propagation of electrical signals in C. elegans neurons requires ion channels capable of regenerating membrane potentials. Here we report regenerative depolarization of a major gustatory sensory neuron, ASEL. Whole-cell patch-clamp recordings in vivo showed supralinear depolarization of ASEL upon current injection. Furthermore, stimulation of animal's nose with NaCl evoked all-or-none membrane depolarization in ASEL. Mutant analysis showed that EGL-19, the α1 subunit of L-type voltage-gated Ca2+ channels, is essential for regenerative depolarization of ASEL. ASEL-specific knock-down of EGL-19 by RNAi demonstrated that EGL-19 functions in C. elegans chemotaxis along an NaCl gradient. These results demonstrate that a natural substance induces regenerative all-or-none electrical signals in dendrites, and that these signals are essential for activation of sensory neurons for chemotaxis. As in other vertebrate and invertebrate nervous systems, active information processing in dendrites occurs in C. elegans, and is necessary for adaptive behavior.