Losartan Prevents Maladaptive Auditory-Somatosensory Plasticity After Hearing Loss via Transforming Growth Factor-β Signaling Suppression

OBJECTIVES: Hearing loss disrupts the balance of auditory-somatosensory inputs in the cochlear nucleus (CN) of the brainstem, which has been suggested to be a mechanism of tinnitus. This disruption results from maladaptive auditory-somatosensory plasticity, which is a form of axonal sprouting. Axonal sprouting is promoted by transforming growth factor (TGF)-β signaling, which can be inhibited by losartan. We investigated whether losartan prevents maladaptive auditory-somatosensory plasticity after hearing loss. METHODS: The study consisted of two stages: determining the time course of auditory-somatosensory plasticity following hearing loss and preventing auditory-somatosensory plasticity using losartan. In the first stage, rats were randomly divided into two groups: a control group that underwent a sham operation and a deaf group that underwent cochlea ablation on the left side. CNs were harvested 1 and 2 weeks after surgery. In the second stage, rats were randomly divided into either a saline group that underwent cochlear ablation on the left side and received normal saline or a losartan group that underwent cochlear ablation on the left side and received losartan. CNs were harvested 2 weeks after surgery. Hearing was estimated with auditory brainstem responses (ABRs). Western blotting was performed for vesicular glutamate transporter 1 (VGLUT1), reflecting auditory input; vesicular glutamate transporter 2 (VGLUT2), reflecting somatosensory input; growth-associated protein 43 (GAP-43), reflecting axonal sprouting; and p-Smad2/3. RESULTS: Baseline ABR thresholds before surgery ranged from 20 to 35 dB sound pressure level. After cochlear ablation, ABR thresholds were higher than 80 dB. In the first experiment, VGLUT2/VGLUT1 ratios did not differ significantly between the control and deaf groups 1 week after surgery. At 2 weeks after surgery, the deaf group had a significantly higher VGLUT2/VGLUT1 ratio compared to the control group. In the second experiment, the losartan group had a significantly lower VGLUT2/VGLUT1 ratio along with significantly lower p-Smad3 and GAP-43 levels compared to the saline group. CONCLUSION: Losartan might prevent axonal sprouting after hearing loss by blocking TGF-β signaling thereby preventing maladaptive auditory-somatosensory plasticity.

Vesicular Glutamate Transporter 1 (VGLUT1)- and VGLUT2-containing Terminals on the Rat Jaw-closing γ-Motoneurons

Currently, compared to jaw-closing (JC) α-motoneurons, the information on the distribution and morphology of glutamatergic synapses on the jaw-closing (JC) γ-motoneurons, which may help elucidate the mechanism of isometric contraction of the JC muscle, is very limited. This study investigated the distribution and ultrastructural features of vesicular glutamate transporter 1 (VGLUT1)- and VGLUT2-immunopositive (+) axon terminals (boutons) on JC γ-motoneurons by retrograde tracing with horseradish peroxidase, electron microscopic immunocytochemistry, and quantitative analysis. About 35% of the boutons on identified JC γ-motoneurons were VGLUT+, and of those, 99% were VGLUT2+. The fraction of VGLUT1+ boutons of all boutons and the percentage of membrane of JC γ-motoneurons covered by these boutons were significantly lower than those for the JC α-motoneurons, revealed in our previous work. The bouton volume, mitochondrial volume, and active zone area of the VGLUT2+ boutons on the JC γ-motoneurons were uniformly small. These findings suggest that the JC γ-motoneurons, in contrast to the JC α-motoneurons, receive generally weak glutamatergic synaptic input almost exclusively from VGLUT2+ premotoneurons that form direct synapse with motoneurons.

Electroacupuncture Alleviates Motor Symptoms and Up-Regulates Vesicular Glutamatergic Transporter 1 Expression in the Subthalamic Nucleus in a Unilateral 6-Hydroxydopamine-Lesioned Hemi-Parkinsonian Rat Model / 神经科学通报·英文版

Previous studies have shown that electroacupuncture (EA) promotes recovery of motor function in Parkinson's disease (PD). However the mechanisms are not completely understood. Clinically, the subthalamic nucleus (STN) is a critical target for deep brain stimulation treatment of PD, and vesicular glutamate transporter 1 (VGluT1) plays an important role in the modulation of glutamate in the STN derived from the cortex. In this study, a 6-hydroxydopamine (6-OHDA)-lesioned rat model of PD was treated with 100 Hz EA for 4 weeks. Immunohistochemical analysis of tyrosine hydroxylase (TH) showed that EA treatment had no effect on TH expression in the ipsilateral striatum or substantia nigra pars compacta, though it alleviated several of the parkinsonian motor symptoms. Compared with the hemi-parkinsonian rats without EA treatment, the 100 Hz EA treatment significantly decreased apomorphine-induced rotation and increased the latency in the Rotarod test. Notably, the EA treatment reversed the 6-OHDA-induced down-regulation of VGluT1 in the STN. The results demonstrated that EA alleviated motor symptoms and up-regulated VGluT1 in the ipsilateral STN of hemi-parkinsonian rats, suggesting that up-regulation of VGluT1 in the STN may be related to the effects of EA on parkinsonian motor symptoms via restoration of function in the cortico-STN pathway.

Disfunción del transportador de glutamato / Glutamate Transporter disfunction

El glutamato, principal neurotransmisor excitatorio, está involucrado en mecanismos de plasticidad sináptica, memoria y muerte neuronal o glial, y el adecuado mantenimiento de sus niveles extracelulares es esencial para evitar la excitotoxicidad. En los últimos años se han producido muchos avances en el estudio de los transportadores de glutamato (VGLUTs y EAATs) encargados de su re-captura en las sinapsis. Haremos una revisión bibliográfica de sus propiedades, alteraciones producidas por su disfunción y posibles alternativas de neuroprotección. Así mismo revisaremos otro aspecto importante, la liberación de glutamato por los astrocitos bajo diversas situaciones patológicas, descubrimiento este de las últimas décadas de investigación sobre la glia

Glutamate, the major excitatory neurotransmitter, is involved in synaptic plasticity, memory and neuronal or glial death, and it is essential to proper maintenance of extracellular levels to prevent excitotoxicity. In recent years there have been many advances in the study of glutamate transporters (EAATs and VGLUTs) responsable for its re-capture at synapses. We will do a bibliographic review of their properties, changes caused by their dysfunction and possible alternatives for neuroprotection. We will also review antoher important aspect, the release of glutamate by astrocytes under different pathological conditions, discovered on the last decades by the research on glia

Role of LRRN3 in the cerebellum postnatal development in rats / 中南大学学报(医学版)

OBJECTIVE@#To explore the effect and possible mechanism of LRRN3 in the cerebellum postnatal development in rats.@*METHODS@#New born rats were randomly divided into an experimental group and a control group, and each group included 3 sub-groups of different time points. Behavioral experiment, hematoxylin-eosin (HE) staining and immunohistochemistry were used to evaluate the effects of anti-LRRN3 injection on the cerebellum development in new born rats.@*RESULTS@#Compared with the control, the balance ability in the experiment group was weak, and there was significant difference in the static balance between the 2 groups (P<0.05). HE staining showed that molecular layer (ML) grew thicker from the 7th day to the 21st day after birth,and the structure changed dynamically. Vesicular glutamate transporter 1(VGluT1) expression was positive in the cerebellum of all groups, and the positive ML grew thicker from the 7th day to the 21st day after birth. Compared with the control, there was no obvious difference between the 2 groups on the 7th day after birth (P<0.05), while on the 14th day and the 21st day, there was significant difference (P<0.01).@*CONCLUSION@#LRRN3 plays an important role in cerebellum postnatal development. Anti-LRRN3 antibody injection may down-regulate the expression of VGluT1, reduce the synapse formation in the molecular layer,decrease the thickness of ML and inhibit the growth of cerebellum cortex and the functional neural circuit formation.