Noise-induced excitotoxicity is thought to depend on glutamate. However, the excitotoxic mechanisms are unknown, and the necessity of glutamate for synapse loss or regeneration is unclear. Despite absence of glutamatergic transmission from cochlear inner hair cells in mice lacking the vesicular glutamate transporter-3 (Vglut3 KO), at 9-11 weeks, approximately half the number of synapses found in Vglut3 WT were maintained as postsynaptic AMPA receptors juxtaposed with presynaptic ribbons and voltage-gated calcium channels (Ca V 1.3). Synapses were larger in Vglut3 KO than Vglut3 WT. In Vglut3 WT and Vglut3 ϩ/Ϫ mice, 8-16 kHz octave-band noise exposure at 100 dB sound pressure level caused a threshold shift (ϳ40 dB) and a loss of synapses (Ͼ50%) at 24 h after exposure. Hearing threshold and synapse number partially recovered by 2 weeks after exposure as ribbons became larger, whereas recovery was significantly better in Vglut3 WT. Noise exposure at 94 dB sound pressure level caused auditory threshold shifts that fully recovered in 2 weeks, whereas suprathreshold hearing recovered faster in Vglut3 WT than Vglut3 ϩ/Ϫ. These results, from mice of both sexes, suggest that spontaneous repair of synapses after noise depends on the level of Vglut3 protein or the level of glutamate release during the recovery period. Noise-induced loss of presynaptic ribbons or postsynaptic AMPA receptors was not observed in Vglut3 KO , demonstrating its dependence on vesicular glutamate release. In Vglut3 WT and Vglut3 ϩ/Ϫ , noise exposure caused unpairing of presynaptic ribbons and presynaptic Ca V 1.3, but not in Vglut3 KO where Ca V 1.3 remained clustered with ribbons at presynaptic active zones. These results suggest that, without glutamate release, noise-induced presynaptic Ca 2ϩ influx was insufficient to disassemble the active zone. However, synapse volume increased by 2 weeks after exposure in Vglut3 KO , suggesting glutamate-independent mechanisms.

Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. Although diagnostic measures and surgical interventions have improved in recent years, the five-year survival rate for patients with advanced HCC remains bleak—a reality that is largely attributable to an absence of early stage symptoms, lack of adequate diagnostic and prognostic biomarkers, and the common occurrence of acquired resistance to chemotherapeutic agents during HCC treatment. A limited understanding of the molecular mechanisms underlying HCC pathogenesis also presents a challenge for the development of specific and efficacious pharmacological strategies to treat, halt, or prevent progression to advanced stages. Over the past decade, aldo-keto reductase family 1 member 10 (AKR1B10) has emerged as a potential biomarker for the diagnosis and prognosis of HCC, and experimental studies have demonstrated roles for this enzyme in biological pathways underlying the development and progression of HCC and acquired resistance to chemotherapeutic agents used in the treatment of HCC. Here we provide an overview of studies supporting the diagnostic and prognostic utility of AKR1B10, summarize the experimental evidence linking AKR1B10 with HCC and the induction of chemoresistance, and discuss the clinical value of AKR1B10 as a potential target for HCC-directed drug development. We conclude that AKR1B10-based therapies in the clinical management of specific HCC subtypes warrant further investigation.

The role of ␣ 1 -adrenergic receptors (␣ 1 ARs) in cognition and mood is controversial, probably as a result of past use of nonselective agents. ␣ 1A AR activation was recently shown to increase neurogenesis, which is linked to cognition and mood. We studied the effects of long-term ␣ 1A AR stimulation using transgenic mice engineered to express a constitutively active mutant (CAM) form of the ␣ 1A AR. CAM-␣ 1A AR mice showed enhancements in several behavioral models of learning and memory. In contrast, mice that have the ␣ 1A AR gene knocked out displayed poor cognitive function. Hippocampal brain slices from CAM-␣ 1A AR mice demonstrated increased basal synaptic transmission, paired-pulse facilitation, and long-term potentiation compared with wild-type (WT) mice. WT mice treated with the ␣ 1A AR-selective agonist cirazoline also showed enhanced cognitive functions. In addition, CAM-␣ 1A AR mice exhibited antidepressant and less anxious phenotypes in several behavioral tests compared with WT mice. Furthermore, the lifespan of CAM-␣ 1A AR mice was 10% longer than that of WT mice. Our results suggest that long-term ␣ 1A AR stimulation improves synaptic plasticity, cognitive function, mood, and longevity. This may afford a potential therapeutic target for counteracting the decline in cognitive function and mood associated with aging and neurological disorders.

Auditory nerve fibers (ANFs) innervating the same inner hair cell (IHC) may have identical frequency tuning but different sound response properties. In cat and guinea pig, ANF response properties correlate with afferent synapse morphology and position on the IHC, suggesting a causal structure-function relationship. In mice, this relationship has not been fully characterized. Here we measured the emergence of synaptic morphological heterogeneities during maturation of the C57BL/6J mouse cochlea by comparing postnatal day 17 (p17, ∼3 days after hearing onset) with p34, when the mouse cochlea is mature. Using serial block face scanning electron microscopy and three-dimensional reconstruction we measured the size, shape, vesicle content, and position of 70 ribbon synapses from the mid-cochlea. Several features matured over late postnatal development. From p17 to p34, presynaptic densities (PDs) and post-synaptic densities (PSDs) became smaller on average (PDs: 0.75 to 0.33; PSDs: 0.58 to 0.31 μm2) and less round as their short axes shortened predominantly on the modiolar side, from 770 to 360 nm. Membrane-associated synaptic vesicles decreased in number from 53 to 30 per synapse from p17 to p34. Anatomical coupling, measured as PSD to ribbon distance, tightened predominantly on the pillar side. Ribbons became less spherical as long-axes lengthened only on the modiolar side of the IHC, from 372 to 541 nm. A decreasing gradient of synaptic ribbon size along the modiolar-pillar axis was detected only at p34 after aligning synapses of adjacent IHCs to a common reference frame (median volumes in nm3 × 106: modiolar 4.87; pillar 2.38). The number of ribbon-associated synaptic vesicles scaled with ribbon size (range 67 to 346 per synapse at p34), thus acquiring a modiolar-pillar gradient at p34, but overall medians were similar at p17 (120) and p34 (127), like ribbon surface area (0.36 vs. 0.34 μm2). PD and PSD morphologies were tightly correlated to each other at individual synapses, more so at p34 than p17, but not to ribbon morphology. These observations suggest that PDs and PSDs mature according to different cues than ribbons, and that ribbon size may be more influenced by cues from the IHC than the surrounding tissue.

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