Agrin-Lrp4 pathway in hippocampal astrocytes restrains development of temporal lobe epilepsy through adenosine signaling.

BACKGROUND: Human patients often experience an episode of serious seizure activity, such as status epilepticus (SE), prior to the onset of temporal lobe epilepsy (TLE), suggesting that SE can trigger the development of epilepsy. Yet, the underlying mechanisms are not fully understood. The low-density lipoprotein receptor related protein (Lrp4), a receptor for proteoglycan-agrin, has been indicated to modulate seizure susceptibility. However, whether agrin-Lrp4 pathway also plays a role in the development of SE-induced TLE is not clear. METHODS: Lrp4f/f mice were crossed with hGFAP-Cre and Nex-Cre mice to generate brain conditional Lrp4 knockout mice (hGFAP-Lrp4-/-) and pyramidal neuron specific knockout mice (Nex-Lrp4-/-). Lrp4 was specifically knocked down in hippocampal astrocytes by injecting AAV virus carrying hGFAP-Cre into the hippocampus. The effects of agrin-Lrp4 pathway on the development of SE-induced TLE were evaluated on the chronic seizure model generated by injecting kainic acid (KA) into the amygdala. The spontaneous recurrent seizures (SRS) in mice were video monitored. RESULTS: We found that Lrp4 deletion from the brain but not from the pyramidal neurons elevated the seizure threshold and reduced SRS numbers, with no change in the stage or duration of SRS. More importantly, knockdown of Lrp4 in the hippocampal astrocytes after SE induction decreased SRS numbers. In accord, direct injection of agrin into the lateral ventricle of control mice but not mice with Lrp4 deletion in hippocampal astrocytes also increased the SRS numbers. These results indicate a promoting effect of agrin-Lrp4 signaling in hippocampal astrocytes on the development of SE-induced TLE. Last, we observed that knockdown of Lrp4 in hippocampal astrocytes increased the extracellular adenosine levels in the hippocampus 2 weeks after SE induction. Blockade of adenosine A1 receptor in the hippocampus by DPCPX after SE induction diminished the effects of Lrp4 on the development of SE-induced TLE. CONCLUSION: These results demonstrate a promoting role of agrin-Lrp4 signaling in hippocampal astrocytes in the development of SE-induced development of epilepsy through elevating adenosine levels. Targeting agrin-Lrp4 signaling may serve as a potential therapeutic intervention strategy to treat TLE.

NRG1-ErbB4 signaling in the medial amygdala controls mating motivation in adult male mice.

Motivation-driven mating is a basic affair for the maintenance of species. However, the underlying molecular mechanisms that control mating motivation are not fully understood. Here, we report that NRG1-ErbB4 signaling in the medial amygdala (MeA) is pivotal in regulating mating motivation. NRG1 expression in the MeA negatively correlates with the mating motivation levels in adult male mice. Local injection and knockdown of MeA NRG1 reduce and promote mating motivation, respectively. Consistently, knockdown of MeA ErbB4, a major receptor for NRG1, and genetic inactivation of its kinase both promote mating motivation. ErbB4 deletion decreases neuronal excitability, whereas chemogenetic manipulations of ErbB4-positive neuronal activities bidirectionally modulate mating motivation. We also identify that the effects of NRG1-ErbB4 signaling on neuronal excitability and mating motivation rely on hyperpolarization-activated cyclic nucleotide-gated channel 3. This study reveals a critical molecular mechanism for regulating mating motivation in adult male mice.

[Effects of different disturbance patterns on stand structure of infected pure Pinus massoniana plantation]. / 不同干扰模式对受害马尾松人工纯林林分结构的影响.

To explore the effects of different disturbance patterns on restoring the health of an infected stand, concentrated disturbance of not cutting trees before 10 years after infection, mode-rate disturbance of cutting infected pine trees, and strong distrubance of cutting infected pine trees, the neighboring trees and poorly growing pine trees were compared in a pure Pinus massomiana plantation infected by Bursaphelenchus xylophlius in Anji, Zhejiang, China. After 16 years, the importance values of P. massoniana in the three treatments were: concentrated disturbance > mode-rate disturbance > strong disturbance. However, the importance values of broad-leaved trees showed the opposite trend. Compared with the concentrated disturbance, the average DBH of P. massoniana in the moderate and strong disturbance treatments were 1.2 and 1.7 times higher, respectively, and those of broad-leaved species were 1.3 and 1.9 times higher, respectively. The average height of pine trees in the moderate and strong disturbance treatments increased 1.5 and 2.0 times, respectively, and those of broad-leaved species 1.2 and 1.8 times, respectively. The tree volume per hectare in moderate and strong disturbance treatments were 5.2 and 3.8 times that of concentrated disturbance treatment, respectively. In the moderate and strong disturbance treatments, the number of trees in each diameter class was greater than in the concentrated disturbance treatment. The stand diameter distribution in the multi-storied moderate and strong disturbance treatments followed an inverse J-shaped curve. The species richness and biodiversity were significantly higher in the mode-rate and strong disturbance treatments than in the concentrated disturbance treatment. The individual size inequality and structural complexity indices followed the order of moderate disturbance > strong disturbance > concentrated disturbance. Under moderate and strong disturbance treatments, the single-storied and evenly aged pure P. massoniana plantation became multi-storied and unevenly aged mixed stands. All the three disturbance patterns promoted the succession of broad-leaved trees, with the pace of succession in the order of strong disturbance > moderate disturbance > concentrated disturbance. In conclusion, moderate disturbance achieved better restoration. Thinning pure P. massoniana plantation could accelerate the succession of a mixed stand to enhance resistance against Bursaphelenchus xylophlius invasion.