Modification of synaptic NMDA receptor (NMDAR) expression influences NMDAR-mediated synaptic function and associated persistent pain. NMDARs directly bind to a family of membrane-associated guanylate kinases (MAGUKs) that regulate surface and synaptic NMDAR trafficking in the CNS. We report here that postsynaptic density-93 protein (PSD-93), a postsynaptic neuronal MAGUK, is expressed abundantly in spinal dorsal horn and forebrain, where it colocalizes and interacts with NMDAR subunits NR2A and NR2B. Targeted disruption of the PSD-93 gene reduces not only surface NR2A and NR2B expression but also NMDAR-mediated excitatory postsynaptic currents and potentials, without affecting surface AMPA receptor expression or its synaptic function, in the regions mentioned above. Furthermore, mice lacking PSD-93 exhibit blunted NMDAR-dependent persistent pain induced by peripheral nerve injury or injection of Complete Freund's Adjuvant, although they display intact nociceptive responsiveness to acute pain. PSD-93 appears to be important for NMDAR synaptic targeting and function and to be a potential biochemical target for the treatment of persistent pain.

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of semitransparent organic solar cells (ST-OSCs) with transparent facilities, such as building windows, automobile glass, and greenhouse rooftops, is of particular interest, since it opens up the prospect of employing the facade for solar-power generation rather than simply employing shadowing and visual functions. [7][8][9][10][11][12] Toward this purpose, ST-OSCs need to generate significant power while still maintaining good transparency and neutral-color perception, which can display a vivid picture when looking through ST-OSCs. [13,14] However, the current performance of ST-OSCs is much lower than their opaque counterparts due to their inherent trade-off between photocurrent and average visible transmittance (AVT) in the range of 380-780 nm. Even worse, these ST-OSCs generally display various colors, making it more difficult to realize high-performance ST-OSCs with promising AVT and neutral color simultaneously. To address the above issues, many efforts have been devoted to the following aspects: (1) developing high-conductivity and high-transparency electrodes to reduce the visible-light reflectance/absorption and contact resistance [15,16] ; (2) synthesizing a nonfullerene acceptor-based photoactive layer with low energy losses and strong near-infrared (NIR) absorption but weak visible absorption to simultaneously increase AVT and power conversion efficiency (PCE) [17][18][19][20][21] ; and (3) incorporating optical engineering to enhance absorption and tuning color conception. [22][23][24][25][26] Based on the above strategies, as shown in Figure 1a, ST-OSCs with promising PCEs of 8%-10% and AVT of over 20% were successfully constructed. [19,[27][28][29] However, the transmitted light still showed strong color bias because of the inhomogeneous device transmittance spectra.To achieve high color-fidelity ST-OSCs for building-integrated photovoltaics application, the light passing through ST-OSCs should maintain the initial component and relative intensity. In other words, the transmittance spectra with flattened, high-transparency, and horizontal characteristics in the visible region can enable neutral-color ST-OSCs. Generally, the color conception of ST-OSCs can be quantified by a color-rendering index (CRI) ranging from 0 to 100 and the color coordinates (x, y) on the Commission Internationale de L'Eclairage (CIE, in French) 1931 color space, where a high CRI value and color coordinates close to AM1.5G (0.35, 0.34) represent neutral-color ST-OSCs. [22,30] Colsmann and co-workers [31] added a red absorbing dye into a top transparent polymeric electrode to compensate for the missing Neutral-colored semitransparent organic solar cells (ST-OSCs) have attracted considerable attention owing to their unique application in no-visual-obstacle building-integrated photovoltaics. Toward this promising potential application, a synergistic effect is first proposed by employing a dielectric mirror and ternary photoactive layer with near-infrared absorption to tune the color perception as well as ST-OSC performance preci...

The perimenopause is an aging transition unique to the female that leads to reproductive senescence which can be characterized by multiple neurological symptoms. To better understand potential underlying mechanisms of neurological symptoms of perimenopause, the current study determined genomic, biochemical, brain metabolic and electrophysiological transformations that occur during this transition using a rat model recapitulating fundamental characteristics of the human perimenopause. Gene expression analyses indicated two distinct aging programs: chronological and endocrine. A critical period emerged during the endocrine transition from regular to irregular cycling characterized by decline in bioenergetic gene expression, confirmed by deficits in FDG-PET brain metabolism, mitochondrial function, and long-term potentiation. Bioinformatic analysis predicted insulin/IGF1 and AMPK/PGC1α signaling pathways as upstream regulators. Onset of acyclicity was accompanied by a rise in genes required for fatty acid metabolism, inflammation, and mitochondrial function. Subsequent chronological aging resulted in decline of genes required for mitochondrial function and β-amyloid degradation. Emergence of glucose hypometabolism and impaired synaptic function in brain provide plausible mechanisms of neurological symptoms of perimenopause and may be predictive of later life vulnerability to hypometabolic conditions such as Alzheimer’s.

PSD-93/chapsin-110 is a neuronal PDZ domain-containing protein that binds to and clusters the N-methyl-D-aspartate receptor (NMDAR) at synapses in the central nervous system. It also assembles a specific set of signaling proteins around the NMDAR and mediates downstream signaling by the NMDAR. Thus, PSD-93/chapsin-110 might be involved in many physiological and pathophysiological actions triggered via the activation of the NMDAR. In the current study, we report that abundant PSD-93/chapsin-110 protein was detected in rat spinal cord, particularly in the superficial dorsal horn. The rats injected intrathecally with PSD-93/chapsin-110 antisense oligodeoxynucleotide every 24 h for 4 days displayed not only a remarkable decrease in spinal cord PSD-93/chapsin-110 expression but also a significant reduction in the paw withdrawal responses to thermal and mechanical stimuli during complete Freund's adjuvant-induced inflammatory pain and peripheral nerve injury-induced neuropathic pain. In contrast, the rats injected intrathecally with PSD-93/chapsin-110 missense oligodeoxynucleotide did not exhibit these changes. We also found that pretreatment with PSD-93/chapsin-110 antisense oligodeoxynucleotide did not change the locomotor activity or the responses to acute noxious thermal and mechanical stimuli in intact rats. The present results indicate that the deficiency of spinal cord PSD-93/chapsin-110 protein significantly attenuates thermal and mechanical hyperalgesia in complete Freund's adjuvant- or peripheral nerve injury-induced chronic pain. This suggests that spinal cord PSD-93/chapsin-110 might be involved in the central mechanism of chronic pain. Our work might provide a new target for the therapy of chronic pain.

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Anesthetics exert multiple effects on the central nervous system through altering synaptic transmission, but the mechanisms for this process are poorly understood. PDZ domain-mediated protein interactions play a central role in organizing signaling complexes around synaptic receptors for efficient signal transduction. We report here that clinically relevant concentrations of inhalational anesthetics dose-dependently and specifically inhibit the PDZ domain-mediated protein interaction between PSD-95 or PSD-93 and the N-methyl-Daspartate receptor or neuronal nitric-oxide synthase. These inhibitory effects are immediate, potent, and reversible and occur at a hydrophobic peptide-binding groove on the surface of the second PDZ domain of PSD-95 in a manner relevant to anesthetic action. These findings reveal the PDZ domain as a new molecular target for inhalational anesthetics.Inhalational anesthetics have been in widespread use for more than 150 years and have been essential in the development of modern surgical procedures, but their molecular mechanisms have remained poorly understood. Early hypotheses based on nonspecific interactions of lipid-soluble anesthetics with the lipid bilayer of neuronal membranes have largely given way to the recent suggestion that anesthetics interact with multiple membrane-associated proteins involved in synaptic transmission (1-5). Inhibitory GABA A and glycine receptors and excitatory N-methyl-D-aspartate (NMDA), 1 nicotinic acetylcholine, and serotonin receptors have been demonstrated as possible physiological targets that underlie general anesthesia (6). Inhalational anesthetics have been shown to both enhance inhibitory receptor-mediated synaptic neurotransmission and depress excitatory receptor-mediated synaptic neurotransmission.Recent studies have revealed a much more complicated picture of excitatory receptor-mediated synaptic transmission than previously anticipated. For efficient synaptic transmission, the downstream effectors are targeted to the receptors by scaffolding proteins via a complex network of protein-protein interactions (7). The PDZ domain is one of the most common protein-protein recognition modules that have been found in diverse scaffolding and signaling proteins (8, 9). The name PDZ derives from the first three proteins (PSD-95/SAP90, Dlg, and ZO-1 (10)) in which these domains were identified. The PDZ domain recognizes specific C-terminal motifs found in target proteins, most often in the cytoplasmic tails of transmembrane receptors and channels (10, 11). The PDZ domain can also recognize structure-related internal motifs to form homo-and heteromeric PDZ-PDZ interactions (12-15). Therefore, PDZ domain-mediated protein-protein interactions provide a framework for the assembly of multiprotein signaling complexes at synapses and neuromuscular junctions. These interactions coordinate and guide the flow of regulatory information and regulate receptor and ion channel activities (16 -19).One of the best understood PDZ domain proteins at synapses is PSD-95, a modula...