Temporal lobe epilepsy causes severe cognitive deficits, but the circuit mechanisms remain unknown. Interneuron death and reorganization during epileptogenesis may disrupt the synchrony of hippocampal inhibition. To test this, we simultaneously recorded from the CA1 and dentate gyrus in pilocarpine-treated epileptic mice with silicon probes during head-fixed virtual navigation. We found desynchronized interneuron firing between the CA1 and dentate gyrus in epileptic mice. Since hippocampal interneurons control information processing, we tested whether CA1 spatial coding was altered in this desynchronized circuit, using a novel wire-free miniscope. We found that CA1 place cells in epileptic mice were unstable and completely remapped across a week. This spatial instability emerged around 6 weeks after status epilepticus, well after the onset of chronic seizures and interneuron death. Finally, CA1 network modeling showed that desynchronized inputs can impair the precision and stability of CA1 place cells. Together, these results demonstrate that temporally precise intrahippocampal communication is critical for spatial processing. David Geffen School of Medicine Dean's Fund for development of open-source miniaturized microscopes to B.

The vitamin D hormone, 1,25dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), and related compounds derived from vitamin D 3 or lumisterol as a result of metabolism via the enzyme CYP11A1, have been shown, when applied 24 hours before or immediately after UV irradiation, to protect human skin cells and skin from DNA damage due to UV exposure, by reducing both cyclobutane pyrimidine dimers (CPD) and oxidative damage in the form of 8-oxo-7,8-dihydro-2 0 -deoxyguanosine (8-OHdG). We now report that knockdown of either the vitamin D receptor or the endoplasmic reticulum protein ERp57 by small, interfering RNA (siRNA) abolished the reductions in UVinduced DNA damage with 20-hydroxyvitamin D 3 or 24-hydroxylumisterol 3, as previously shown for 1,25(OH) 2 D 3 . Treatment with 1,25(OH) 2 D 3 reduced oxygen consumption rates in UV-exposed and sham-exposed human keratinocytes and reduced phosphorylation of cyclic AMP response binding element protein (CREB). Both these actions have been shown to inhibit skin carcinogenesis after chronic UV exposure, consistent with the anticarcinogenic activity of 1,25(OH) 2 D 3 . The requirement for a vitamin D receptor for the photoprotective actions of 1,25(OH) 2 D 3 and of naturally occurring CYP11A1-derived vitamin D-related compounds may explain why mice lacking the vitamin D receptor in skin are more susceptible to UV-induced skin cancers, whereas mice lacking the 1αhydroxylase and thus unable to make 1,25(OH) 2 D 3 are not more susceptible.

No abstract

The epidermis maintains a cellular calcium gradient that supports keratinocyte differentiation from its basal layers (low) to outer layers (high) leading to the development of the stratum corneum, which resists penetration of UV radiation. The calcium-sensing receptor (CaSR) expressed in keratinocytes responds to the calcium gradient with signals that promote differentiation. In this study, we investigated whether the CaSR is involved more directly in protection from UV damage in studies of human keratinocytes in primary culture and in mouse skin studied in vivo. siRNA-directed reductions in CaSR protein levels in human keratinocytes significantly reduced UV-induced direct cyclobutane pyrimidine dimers (CPD) by ~80% and oxidative DNA damage (8-OHdG) by ~65% compared with control transfected cells. Similarly, in untransfected cells, the CaSR negative modulator, NPS-2143 (500 nM), reduced UV-induced CPD and 8-OHdG by ~70%. NPS-2143 also enhanced DNA repair and reduced reactive oxygen species (ROS) by ~35% in UV-exposed keratinocytes, consistent with reduced DNA damage after UV exposure. Topical application of NPS-2143 also protected hairless Skh: hr1 mice from UV-induced CPD, oxidative DNA damage and inflammation, similar to the reductions observed in response to the well-known photoprotection agent 1,25(OH) 2 D 3 (calcitriol). Thus, negative modulators of the CaSR offer a new approach to reducing UV-induced skin damage.

Transition of electric activity of neuron can be induced by electric autapse, and its action potential is much sensitive to the stimuli from the electric autapse. Generally, the effect of electric autapse on membrane potential of neuron is often described by using time-delayed feedback in closed loop. Based on Pspice software, a class of electric circuit is designed with the electric autapse being taken into consideration, and a time-delayed circuit is used to detect the adjusting action of electric autapse on the action potential. Results are found as follows: (1) The neuronal electric circuit can produce quiescent state, spiking, bursting state under an external force besides the electric autapse circuit. (2) The transition of electric activity occurs between four different atates (quiescent, spiking, bursting state) by imposing a time-varying forcing current; its potential mechanism is that the electric circuit is associated with the memory, and the neuron can give different types of response to the same external forcing current. (3)When a strong external force is imposed, the outputs can show different type of electric activities due to an electric autapse, that is to say, self-adaption of gain in the autapse is useful for the neuron and thus different type of electric activities occurs, whose potential mechanism may be due to the effective feedback in the loop; so it is helpful to understand the synaptic plasticity.