Neuroplasticity forms the basis for neuronal circuit complexity and differences between otherwise similar circuits. We show that the microphthalmia-associated transcription factor (Mitf) plays a central role in intrinsic plasticity of olfactory bulb (OB) projection neurons. Mitral and tufted (M/T) neurons from Mitf mutant mice are hyperexcitable, have a reduced A-type potassium current (I A) and exhibit reduced expression of Kcnd3, which encodes a potassium voltage-gated channel subunit (Kv4.3) important for generating the I A. Furthermore, expression of the Mitf and Kcnd3 genes is activity dependent in OB projection neurons and the MITF protein activates expression from Kcnd3 regulatory elements. Moreover, Mitf mutant mice have changes in olfactory habituation and have increased habituation for an odorant following long-term exposure, indicating that regulation of Kcnd3 is pivotal for long-term olfactory adaptation. Our findings show that Mitf acts as a direct regulator of intrinsic homeostatic feedback and links neuronal activity, transcriptional changes and neuronal function.
IntroductionA hallmark of photoreceptor degenerations is progressive, aberrant remodeling of the surviving retinal neurons and glia following photoreceptor loss. The exact relationship between neurons and glia remodeling in this late stage of retinal degeneration, however, is unclear. This study assessed this by examining Müller cell dysfunction via glutamine synthetase immunoreactivity and its spatial association with retinal neuron subpopulations through various cell markers.MethodsAged Rd1 mice retinae (P150 – P536, n = minimum 5 per age) and control heterozygous rd1 mice retinae (P536, n = 5) were isolated, fixed and cryosectioned. Fluorescent immunolabeling of glutamine synthetase was performed and retinal areas quantified as having low glutamine synthetase immunoreactivity if proportion of labeled pixels in an area was less than two standard deviations of the mean of the total retina. Other Müller cell markers such as Sox9 and Glial fibrillary acidic protein along with neuronal cell markers Calbindin, Calretinin, recoverin, Protein kinase C-α, Glutamic acid decarboxylase 67, and Islet-1 were then quantified within areas of low and normal synthetase immunoreactivity.ResultsGlutamine synthetase immunoreactivity was lost as a function of age in the rd1 mouse retina (P150 – P536). Immunoreactivity of other Müller cell markers, however, were unaffected suggesting Müller cells were still present in these low glutamine synthetase immunoreactive regions. Glutamine synthetase immunoreactivity loss affected specific neuronal populations: Type 2, Type 8 cone, and rod bipolar cells, as well as AII amacrine cells based on reduced recoverin, protein kinase Ca and parvalbumin immunoreactivity, respectively. The number of cell nuclei within regions of low glutamine synthetase immunoreactivity was also reduced suggesting possible neuronal loss rather than reduced cell marker immunoreactivity.ConclusionThese findings further support a strong interplay between glia-neuronal alterations in late-stage degeneration and highlight a need for future studies and consideration in intervention development.
Purpose: Mice carrying pathogenic variants in the microphthalmia transcription factor (Mitf) gene show structural and functional changes in the retina and retinal pigment epithelium. The purpose of this study was to assess the vascular changes in Mitf mice carrying pathogenic variants by determining their retinal vessel diameter. Methods: Mice examined in this study were: B6-Mitf mi-vga9/+ (n = 6), B6-Mitf mi-enu22(398) /Mitf mi-enu22(398) (n = 6) and C57BL/6J wild type mice (n = 6), all 3 months old. Fundus images were taken with a Micron IV camera after intraperitoneal injection of fluorescein salt. Images were adjusted to enhance contrast and a custom written MATLAB program used to extract the mean vascular diameter at a pre-defined distance from the optic disc. The number of vessels, mean diameter and mean total diameter were examined. Results: The mean diameter of retinal veins in Mitf mi-enu22(398) /Mitf mi-enu22(398) mice was 18.8% larger than in wild type (p = 0.026). No differences in the mean diameter of the retinal arteries were found between the genotypes. Mitf mi-enu22(398) /Mitf mi-enu22(398) mice have 17.2% more retinal arteries (p = 0.026), and 15.6% more retinal veins (p = 0.041) than wild type. A 24.8% increase was observed in the mean combined arterial diameter in mice with the Mitf mi-enu22(398)/ Mitf mi-enu22(398) compared to wild type mice (p = 0.024). A 38.6% increase was found in the mean combined venular diameter in mice with the Mitf mi-enu22(398) /Mitf mi-enu22(398) pathogenic variation as compared to wild type (p = 0.004). The mean combined retinal venular diameter in the Mitf mi-vga9/+ mice was 17.8% larger than in wild type (p = 0.03). Conclusion: An increase in vascularization of the retina in Mitf mi-enu22(398) / Mitf mi-enu22(398) mice was found, indicating an increased demand for blood flow to the retina.
for their help. Significance statementThese findings broaden the general understanding of transcriptional regulation of intrinsic plasticity in learning and memory. Regulation of intrinsic plasticity has wide-ranging implications and fundamental importance for neurological diseases.
In the current study activity and latency to explore, as well as the correlation of these traits, were examined in individually marked juvenile Gadus morhua at 7, 10 and 13° C. It was concluded that individual rank order of both traits was maintained across temperature but that the level of change differed between individuals.
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