Increased phosphorylation of Cx36 gap junctions in the AII amacrine cells of RD retina

Retinal degeneration (RD) encompasses a family of diseases that lead to photoreceptor death and visual impairment. Visual decline due to photoreceptor cell loss is further compromised by emerging spontaneous hyperactivity in inner retinal cells. This aberrant activity acts as a barrier to signals from the remaining photoreceptors, hindering therapeutic strategies to restore light sensitivity in RD. Gap junctions, particularly those expressed in AII amacrine cells, have been shown to be integral to the generation of aberrant activity. It is unclear whether gap junction expression and coupling are altered in RD. To test this, we evaluated the expression and phosphorylation state of connexin36, the gap junction subunit predominantly expressed in AII amacrine cells, in two mouse models of RD, rd10 (slow degeneration) and rd1 (fast degeneration). Using Ser293-P antibody, which recognizes a phosphorylated form of connexin36, we found that phosphorylation of connexin36 in both slow and fast RD models was significantly greater than in wildtype controls. This elevated phosphorylation may underlie the increased gap junction coupling of AII amacrine cells exhibited by RD retina

Network Deficiency Exacerbates Impairment in a Mouse Model of Retinal Degeneration

Neural oscillations play an important role in normal brain activity, but also manifest during Parkinson’s disease, epilepsy, and other pathological conditions. The contribution of these aberrant oscillations to the function of the surviving brain remains unclear. In recording from retina in a mouse model of retinal degeneration (RD), we found that the incidence of oscillatory activity varied across different cell classes, evidence that some retinal networks are more affected by functional changes than others. This aberrant activity was driven by an independent inhibitory amacrine cell oscillator. By stimulating the surviving circuitry at different stages of the neurodegenerative process, we found that this dystrophic oscillator further compromises the function of the retina. These data reveal that retinal remodeling can exacerbate the visual deficit, and that aberrant synaptic activity could be targeted for RD treatment

Nonlinear interactions between excitatory and inhibitory retinal synapses control visual output

The visual system is highly sensitive to dynamic features in the visual scene. However, it is not known how or where this enhanced sensitivity first occurs. We investigated this phenomenon by studying interactions between excitatory and inhibitory synapses in the second synaptic layer of the mouse retina. We found that these interactions showed activity-dependent changes that enhanced signaling of dynamic stimuli. Excitatory signaling from cone bipolar cells to ganglion cells exhibited strong synaptic depression, attributable to reduced glutamate release from bipolar cells. This depression was relieved by amacrine cell inhibitory feedback that activated presynaptic GABA(C) receptors. We found that the balance between excitation and feedback inhibition depended on stimulus frequency; at short interstimulus intervals excitation was enhanced, attributable to reduced inhibitory feedback. This dynamic interplay may enrich visual processing by enhancing retinal responses to closely spaced temporal events, representing rapid changes in the visual environment

Ablation of mouse adult neurogenesis alters olfactory bulb structure and olfactory fear conditioning

Adult neurogenesis replenishes olfactory bulb (OB) interneurons throughout the life of most mammals, yet during this constant fl ux it remains unclear how the OB maintains a constant structure and function. In the mouse OB, we investigated the dynamics of turnover and its impact on olfactory function by ablating adult neurogenesis with an x-ray lesion to the subventricular zone (SVZ). Regardless of the magnitude of the lesion to the SVZ, we found no change in the survival of young adult born granule cells (GCs) born after the lesion, and a gradual decrease in the population of GCs born before the lesion. After a lesion producing a 96% reduction of incoming adult born GCs to the OB, we found a diminished behavioral fear response to conditioned odor cues but not to audio cues. Interestingly, despite this behavioral defi cit and gradual anatomical changes, we found no electrophysiological changes in the GC population assayed in vivo through dendro-dendritic synaptic plasticity and odor-evoked local fi eld potential oscillations. These data indicate that turnover in the granule cell layer is generally decoupled from the rate of adult neurogenesis, and that OB adult neurogenesis plays a role in a wide behavioral system extending beyond the OB

Calcium imaging reveals wave-like activity in adult retina that is suppressed by an inhibitory network.

<p>A: left panel, A fluorescence image showing loading of calcium indicator OGB-1-AM (green) with superimposed GC (red). Dashed lines indicate position of the recording pipette. Arrowhead points to GC axon. Dark shadow in the left is a blood vessel. Scale bar 80 µm. (A, middle panel) Simultaneous calcium imaging (top) and whole-cell sEPSC traces from GC (bottom). (A, right panel) Cross-correlations between ΔF/F and sEPSCs (right, n = 21) and randomized controls. Note inversed Y-axis to reflect the opposite directions for correlated events – each increase in intracellular calcium (positive) coincides with an inward current (negative). B: A sequence of ΔF/F pseudo color time-lapse images during 12 s of retinal activity viewed from GC side at P47. Blockade of inhibitory feedback reveals the wave-like propagating activity across the retina (middle). This activity is not evident in untreated control conditions (top) and eliminated by application of nifedipine (bottom), a selective antagonist of L-type VGCaCs. Size of the retinal region in each panel is 636× µm. C: Time course of the ΔF/F monitored over 120 s from retinal region marked by a white box in B at various conditions. D: Histogram of wave velocities under SST condition. Bin size is 100 µm/s, n = 130 of waves and n = 4 of retinas. See Supplementary <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077658#pone.0077658.s001" target="_blank">Videos S1</a>–<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077658#pone.0077658.s004" target="_blank">4</a> for calcium recordings during control, SST and nifedipine conditions in raw (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077658#pone.0077658.s001" target="_blank">Videos S1</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077658#pone.0077658.s002" target="_blank">S2</a>) and ΔF/F pseudo color modes (<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077658#pone.0077658.s003" target="_blank">Videos S3</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077658#pone.0077658.s004" target="_blank">S4</a>) from P47 retinas.</p

Developmental changes in the effect of cholinergic, inhibitory and L-type voltage-gated calcium channel-dependent networks on spontaneous activity.

<p>A: sEPSCs recorded from GCs at different ages in control and following the blockade of nicotinic AChRs, inhibitory transmission and L-type VGCaCs. B and C: Summary graphs of GC activity and the contribution of different receptors over age. Early in postnatal development (P5–6) the activity is mediated by AChRs and blocked by DHβE/curarine. At second postnatal week, the contribution of AChRs is reduced. In contrast, regenerative compound activity revealed by SST is more prominent with age, as BC axons and inhibitory inputs mature and spontaneous currents decrease (C, red and black traces). This transition is most prominent in late second postnatal week (see text and <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0077658#pone-0077658-t001" target="_blank">Table 1</a> for details). All data are reported as means ± SEM.</p