SUMMARY Resilience of neural circuits has been observed in the persistence of function despite neuronal loss. In vision, acuity and sensitivity can be retained after 50% loss of cones. While neurons in the cortex can remodel after input loss, the contributions of cell-type-specific circuits to resilience are unknown. Here, we study the effects of partial cone loss in mature mouse retina where cell types and connections are known. At first-order synapses, bipolar cell dendrites remodel and synaptic proteins diminish at sites of input loss. Sites of remaining inputs preserve synaptic proteins. Second-order synapses between bipolar and ganglion cells remain stable. Functionally, ganglion cell spatio-temporal receptive fields retain center-surround structure following partial cone loss. We find evidence for slower temporal filters and expanded receptive field surrounds, derived mainly from inhibitory inputs. Surround expansion is absent in partially stimulated control retina. Results demonstrate functional resilience to input loss beyond pre-existing mechanisms in control retina.

SUMMARY Loss of primary neuronal inputs inevitably strikes every neural circuit. The deafferented circuit could propagate, amplify, or mitigate input loss, thus affecting the circuit’s output. How the deafferented circuit contributes to the effect on the output is poorly understood because of lack of control over loss of and access to circuit elements. Here, we control the timing and degree of rod photoreceptor ablation in mature mouse retina and uncover compensation. Following loss of half of the rods, rod bipolar cells mitigate the loss by preserving voltage output. Such mitigation allows partial recovery of ganglion cell responses. We conclude that rod death is compensated for in the circuit because ganglion cell responses to stimulation of half of the rods in an unperturbed circuit are weaker than responses after death of half of the rods. The dominant mechanism of such compensation includes homeostatic regulation of inhibition to balance the loss of excitation.

ObjectiveTo compare the sensitivity of gadolinium MRI inner imaging with tone burst electrocochleography (EcochG) for diagnosing endolymphatic hydrops.Study DesignA prospective study on patients who were to have an MRI scan to exclude retrocochlear pathology.SettingTertiary care center.PatientsOne hundred and two patients: 57 patients with Possible, Probable, or Definite Ménière’s Disease, 25 with asymmetrical hearing loss, 18 with sudden sensorineural hearing loss, and 2 with unilateral tinnitus had additional MRI inner ear imaging and click and tone burst stimulus EcochG testing.InterventionDiagnostic.Main Outcome MeasureTo compare the sensitivity of the two techniques.ResultsIn 30 patients with symptom-based Definite Ménière’s Disease, tone burst EcochG was positive in 25 (83%) and the click EcochG was positive in 9/30 (30%), and gadolinium MRI imaging diagnosed hydrops in 14 (47%). A positive result for either MRI imaging or tone burst EcochG was seen in 26 patients (87%). In 14 subjects with symptom-based Probable Ménière’s Disease, 10 (71%) had either a positive EcochG or MRI. In 13 with Possible Ménière’s Disease, four (31%) had a positive EcochG or MRI.ConclusionThis study confirms the greatly enhanced diagnostic sensitivity of tone burst EcochG over click response in diagnosing endolymphatic hydrops in Ménière’s disease. Even though adequate MRI imaging was achieved in 90%, tone burst EcochG was a more sensitive test.

Soil bacteria like Bacillus subtilis can cope with many growth conditions by adjusting gene expression and metabolic pathways. Alternatively, bacteria can spontaneously accumulate beneficial mutations or shape their genomes in response to stress. Recently, it has been observed that a B. subtilis mutant lacking the catabolically active glutamate dehydrogenase (GDH), RocG, mutates the cryptic gudBCR gene at a high frequency. The suppressor mutants express the active GDH GudB, which can fully replace the function of RocG. Interestingly, the cryptic gudBCR allele is stably inherited as long as the bacteria synthesize the functional GDH RocG. Competition experiments revealed that the presence of the cryptic gudBCR allele provides the bacteria with a selective growth advantage when glutamate is scarce. Moreover, the lack of exogenous glutamate is the driving force for the selection of mutants that have inactivated the active gudB gene. In contrast, two functional GDHs are beneficial for the cells when glutamate was available. Thus, the amount of GDH activity strongly affects fitness of the bacteria depending on the availability of exogenous glutamate. At a first glance the high mutation frequency of the cryptic gudBCR allele might be attributed to stress-induced adaptive mutagenesis. However, other loci on the chromosome that could be potentially mutated during growth under the selective pressure that is exerted on a GDH-deficient mutant remained unaffected. Moreover, we show that a GDH-proficient B. subtilis strain has a strong selective growth advantage in a glutamate-dependent manner. Thus, the emergence and rapid clonal expansion of the active gudB allele can be in fact explained by spontaneous mutation and growth under selection without an increase of the mutation rate. Moreover, this study shows that the selective pressure that is exerted on a maladapted bacterium strongly affects the apparent mutation frequency of mutational hot spots.

The Gram-positive model bacterium Bacillus subtilis contains two glutamate dehydro genase-encoding genes, rocG and gudB. While the rocG gene encodes the functional GDH, the gudB gene is cryptic (gudBCR) in the laboratory strain 168 due to a perfect 18 bp-long direct repeat that renders the GudB enzyme inactive and unstable. Although constitutively expressed the GudBCR protein can hardly be detected in B. subtilis as it is rapidly degraded within stationary growth phase. Its high instability qualifies GudBCR as a model substrate for studying protein turnover in B. subtilis. Recently, we have developed a visual screen to monitor the GudBCR stability in the cell using a GFP-GudBCR fusion. Using fluorescent microscopy we found that the GFP protein is simultaneously degraded together with GudBCR. This allows us to analyze the stability of GudBCR in living cells. By combining the visual screen with a transposon mutagenesis approach we looked for mutants that show an increased fluorescence signal compared to the wild type indicating a stabilized GFP-GudBCR fusion. We observed, that disruption of the arginine kinase encoding gene mcsB upon transposon insertion leads to increased amounts of the GFP-GudBCR fusion in this mutant. Deletion of the cognate arginine phosphatase YwlE in contrast results in reduced levels of the GFP-GudBCR fusion. Recently, it was shown that the kinase McsB is involved in phosphorylation of GudBCR on arginine residues. Here we show that selected arginine-lysine point mutations of GudBCR exhibit no influence on degradation. The activity of McsB and YwlE, however, are crucial for the activation and inhibition, respectively, of a proteolytic machinery that efficiently degrades the unstable GudBCR protein in B. subtilis.