nGnG Amacrine Cells and Brn3b-negative M1 ipRGCs are Specifically Labeled in the ChAT-ChR2-EYFP Mouse.

Purpose: Experimental access to specific cell subtypes is essential for deciphering the complexity of retinal networks. Here, we characterized the selective labeling, caused by ectopic transgene expression, of two atypical retinal neurons in the ChAT-Channelrhodopsin-2 (ChR2)-EYFP mouse. Methods: Retinal sections and flat-mounts were prepared for double-staining immunohistochemistry with antibodies against EYFP and various neuronal markers. Sagittal/coronal brain slices were made to visualize EYFP signals in central nuclei. Whole-cell recordings were conducted to test the functionality of ChR2. Results: Two populations of EYFP-positive retinal cells were observed. The inner nuclear layer (INL)-located one (type I cell) distributed regularly throughout the entire retina, whereas the ganglion cell layer (GCL)-residing one (type II cell) was restricted ventrally. None of them was cholinergic, as evidenced by the complete absence of ChAT immunoreactivity. Type I cells were immunolabeled by the amacrine marker syntaxin. However, the vast majority of them were neither positive to GABA/GAD65, nor to GlyT1/glycine, suggesting that they were non-GABAergic non-glycinergic amacrine cells (nGnG ACs), which was confirmed by double-labeling with the nGnG AC marker PPP1R17. Type II cells were immunopositive to melanopsin, but not to Brn3a or Brn3b. They possessed dendrites stratifying in the outermost inner plexiform layer (IPL) and axons projecting to the suprachiasmatic nucleus (SCN) rather than the olivary pretectal nucleus (OPN), suggesting that they belonged to a Brn3b-negative subset of M1-type intrinsically photosensitive retinal ganglion cells (ipRGCs). Glutamatergic transmission-independent photocurrents were elicited in EYFP-positive cells, indicating the functional expression of ChR2. Conclusions: The ChAT-ChR2-EYFP retina exhibits ectopic, but functional, transgene expression in nGnG ACs and SCN-innervating M1 ipRGCs, thus providing an ideal tool to achieve efficient labeling and optogenetic manipulation of these cells.

BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction.

BACKGROUND: Depression is thought to be multifactorial in etiology, including genetic and environmental components. While a number of gene-environment interaction studies have been carried out, meta-analyses are scarce. The present meta-analysis aimed to quantify evidence on the interaction between brain-derived neurotrophic factor (BDNF) Val66Met polymorphism and stress in depression. METHODS: Included were 31 peer-reviewed with a pooled total of 21060 participants published before October 2016 and literature searches were conducted using PubMed, Wolters Kluwer, Web of Science, EBSCO, Elsevier Science Direct and Baidu Scholar databases. RESULTS: The results indicated that the Met allele of BDNF Val66Met polymorphism significantly moderated the relationship between stress and depression (Z=2.666, p = 0.003). The results of subgroup analysis concluded that stressful life events and childhood adversity separately interacted with the Met allele of BDNF Val66Met polymorphism in depression (Z = 2.552, p = 0.005; Z = 1.775, p = 0.03). LIMITATIONS: The results could be affected by errors or bias in primary studies which had small sample sizes with relatively lower statistic power. We could not estimate how strong the interaction effect between gene and environment was. CONCLUSIONS: We found evidence that supported the hypothesis that BDNF Val66Met polymorphism moderated the relationship between stress and depression, despite the fact that many included individual studies did not show this effect.

Meta-analysis of the interaction between serotonin transporter promoter variant, stress, and posttraumatic stress disorder.

Exposure to stress predicts the occurrence of posttraumatic stress disorder (PTSD) in individuals harboring the serotonin transporter promoter variant 5-HTTLPR. We carried out a meta-analysis of studies investigating the interaction between 5-HTTLPR, stress, and PTSD to clarify the interrelatedness of these factors. We reviewed all relevant studies published in English before May 2016. The Lipták-Stouffer z-score method for meta-analysis was applied to combined data. The z score was separately calculated for the stressful life events, childhood adversity, bi- and triallelic loci, and cross-sectional and longitudinal studies subgroups. A total of 14 studies with 15,883 subjects met our inclusion criteria. We found strong evidence that the presence of 5-HTTLPR influenced the relationship between stress and PTSD (P = 0.00003), with the strongest effects observed in the cross-sectional and longitudinal groups (P = 0.01 and 2.0 × 10-6, respectively). Stressful life events and childhood adversity separately interacted with 5-HTTLPR in PTSD (P = 2.0 × 10-8 and 0.003, respectively). When the studies were stratified by locus classification, the evidence was stronger for the triallelic (P = 4.0 × 10-8) than for the biallelic (P = 0.054) locus subgroup. There was strong evidence that 5-HTTLPR influences the relationship between stress and PTSD.

Mismatch negativity as a potential neurobiological marker of early-stage Alzheimer disease and vascular dementia.

Alzheimer's disease (AD) and vascular dementia (VD) are serious, irreversible forms of cognitive impairment, which means that an early diagnosis is essential to slow down their progression. One potential neurophysiological biomarker of these diseases is the mismatch negativity (MMN) event-related potentials (ERP) component, which reflects an automatic detection mechanism at the pre-attentive stages of information processing. We evaluated the auditory MMN response in individuals from two patient groups: those in the prodromal stages of AD (P-AD) and those in the prodromal stages of VD (P-VD). Thirty patients (15 P-AD patients and 15 P-VD patients) and 30 age-matched controls were recruited to undergo electrophysiological recordings during the presentation of an auditory deviant-standard-reverse oddball paradigm that was used to elicit genuine MMN responses. We show that over the frontal-central area, the mean amplitude of the MMN was significantly reduced in both the P-AD (p=0.017) and P-VD groups (p=0.013) compared with controls. The MMN peak latency in P-VD patients was significantly shorter than in controls (p=0.027). No MMN response differences between the P-AD and P-VD were found in either the frontal-central or the temporal areas. These results indicate that P-AD and P-VD patients exhibit impaired pre-attentive information processing mechanisms as revealed by the frontal-central area MMN response, which is associated with sensory memory and cognitive deficits.

Using event-related potential P300 as an electrophysiological marker for differential diagnosis and to predict the progression of mild cognitive impairment: a meta-analysis.

P300 event-related potential component may sensitively predict mild cognitive impairment (MCI) progression. Here, pooled effect size estimates of P300 amplitude and latency were computed at midline electrodes among controls, MCI patients, and Alzheimer's disease (AD) patients. Baseline data were compared to one-year follow-up data. MCI patients showed decreased P300 amplitude and prolonged latency compared to controls. Pooled standardized mean differences (SMDs) were -0.67 (95 % CI -1.12 to -0.23, P = 0.003) and 0.90 (95 % CI 0.66-1.14, P < 0.00001), respectively. P300 latency decreased in MCI compared to AD patients where the pooled SMD was -0.52 (95 % CI -0.85 to -0.18, P = 0.003). Amplitude and latency differed between MCI baseline and follow-up. Pooled SMDs were 0.47 (95 % CI 0.29 to -0.65, P < 0.00001) and -0.52 (95 % CI -0.71 to -0.34, P < 0.00001), respectively. Group differences in MCI P300 latency existed compared to control and AD patients. P300 latency may therefore be a sensitive indicator for early cognitive decline or disease progression in MCI patients and identifying elderly patient progression to MCI and/or AD.

Group I mGluR-mediated inhibition of Kir channels contributes to retinal Müller cell gliosis in a rat chronic ocular hypertension model.

Müller cell gliosis, which is characterized by upregulated expression of glial fibrillary acidic protein (GFAP), is a universal response in many retinal pathological conditions. Whether down-regulation of inward rectifying K+ (Kir) channels, which commonly accompanies the enhanced GFAP expression, could contribute to Müller cell gliosis is poorly understood. We investigated changes of Kir currents, GFAP and Kir4.1 protein expression in Müller cells in a rat chronic ocular hypertension (COH) model, and explored the mechanisms underlying Müller cell gliosis. We show that Kir currents and Kir4.1 protein expression in Müller cells were reduced significantly, while GFAP expression was increased in COH rats, and these changes were eliminated by MPEP, a group I metabotropic glutamate receptors (mGluR I) subtype mGluR5 antagonist. In normal isolated Müller cells, the mGluR I agonist (S)-3,5-dihydroxyphenylglycine (DHPG) suppressed the Kir currents and the suppression was blocked by MPEP. The DHPG effect was mediated by the intracellular Ca2+ -dependent PLC/IP3-ryanodine/PKC signaling pathway, but the cAMP-PKA pathway was not involved. Moreover, intravitreal injection of DHPG in normal rats induced changes in Müller cells, similar to those observed in COH rats. The DHPG-induced increase of GFAP expression in Müller cells was obstructed by Ba2+, suggesting the involvement of Kir channels. We conclude that overactivation of mGluR5 by excessive extracellular glutamate in COH rats could contribute to Müller cell gliosis by suppressing Kir channels.

Distribution of somatostatin receptor 5 in mouse and bullfrog retinas.

Somatostatin (SRIF), as a neuroactive peptide in the CNS, may act as a neuromodulator through activation of five specific receptor subtypes (sst(1)-sst(5)). In this work we conducted a comparative study of the expression of sst(5) in mouse and bullfrog retinas by immunofluorescence double labeling. Basically, the expression profiles of sst(5) in the retinas of the two species were similar. That is, in the inner retina sst(5) was localized to dopaminergic and cholinergic amacrine cells, stained by tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) respectively, and cells in the ganglion cell layer, whereas in the outer retina immunostaining for sst(5) was observed in horizontal cells. However, a more widespread, abundant distribution of labeling for sst(5), as compared to mouse retina, was seen in bullfrog retina: strong labeling for sst(5) was diffusely distributed in both outer and inner plexiform layers (OPL and IPL) in the bullfrog retina, but the labeling was only observed in the IPL of the mouse retina. In addition, bullfrog photoreceptors, both rods and cones, but not mouse ones, were labeled by sst(5). In combination with the experiments showing that SRIF-immunoreactivity was mainly found in the inner retina, our results suggest that SRIF, released from SRIF-containing cells in the inner retina, may play a neuromodulatory role in both outer and inner retina mediated by volume transmission via sst(5) in bullfrog retina, while the SRIF action may be largely restricted to the mouse inner retina.

σ receptor 1 is preferentially involved in modulation of N-methyl-D-aspartate receptor-mediated light-evoked excitatory postsynaptic currents in rat retinal ganglion cells.

Using patch-clamp whole-cell recording, we investigated how activation of the sigma receptor 1 (σR1) modulates light-evoked excitatory postsynaptic currents (eEPSCs) of ganglion cells (GCs) in rat retinal slice preparations. Bath application of the σR1 agonist SKF10047 (SKF) suppressed N-methyl-D-aspartate (NMDA) receptor-mediated eEPSCs at different holding potentials in ON, OFF and ON-OFF GCs, and the effects were blocked when the preparations were pre-incubated with the σR1 antagonist BD1047. In contrast, SKF had no effects on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor-mediated eEPSCs of these GCs. Furthermore, application of SKF did not affect AMPA receptor-mediated miniature EPSCs of GCs, suggesting that activation of σR1 did not change the release of glutamate from bipolar cells. These results suggest that σR1 may be involved in the regulation of output signaling of GCs by preferentially modulating NMDA receptor-mediated eEPSCs of these retinal neurons.