RESUMEN
Dendrites are injured in a variety of clinical conditions such as traumatic brain and spinal cord injuries and stroke. How neurons detect injury directly to their dendrites to initiate a pro-regenerative response has not yet been thoroughly investigated. Calcium plays a critical role in the early stages of axonal injury detection and is also indispensable for regeneration of the severed axon. Here, we report cell and neurite type-specific differences in laser injury-induced elevations of intracellular calcium levels. Using a human KCNJ2 transgene, we demonstrate that hyperpolarizing neurons only at the time of injury dampens dendrite regeneration, suggesting that inhibition of injury-induced membrane depolarization (and thus early calcium influx) plays a role in detecting and responding to dendrite injury. In exploring potential downstream calcium-regulated effectors, we identify L-type voltage-gated calcium channels, inositol triphosphate signaling, and protein kinase D activity as drivers of dendrite regeneration. In conclusion, we demonstrate that dendrite injury-induced calcium elevations play a key role in the regenerative response of dendrites and begin to delineate the molecular mechanisms governing dendrite repair.
Asunto(s)
Calcio , Dendritas , Regeneración Nerviosa , Dendritas/metabolismo , Dendritas/fisiología , Animales , Calcio/metabolismo , Regeneración Nerviosa/fisiología , Humanos , Ratones , Canales de Potasio de Rectificación Interna/metabolismo , Ratones TransgénicosRESUMEN
The neurobiology of autism has been shown to involve alterations in cortical morphology and gamma-aminobutyric acid A (GABAA ) receptor density. We hypothesized that GABAA receptor binding potential (GABAA R BPND ) would correlate with cortical thickness, but their correlations would differ between autistic adults and typically developing (TD) controls. We studied 50 adults (23 autism, 27 TD, mean age of 27 years) using magnetic resonance imaging to measure cortical thickness, and [18 F]flumazenil positron emission tomography imaging to measure GABAA R BPND . We determined the correlations between cortical thickness and GABAA R BPND by cortical lobe, region-of-interest, and diagnosis of autism spectrum disorder (ASD). We also explored potential sex differences in the relationship between cortical thickness and autism characteristics, as measured by autism spectrum quotient (AQ) scores. Comparing autism and TD groups, no significant differences were found in cortical thickness or GABAA R BPND . In both autism and TD groups, a negative relationship between cortical thickness and GABAA R BPND was observed in the frontal and occipital cortices, but no relationship was found in the temporal or limbic cortices. A positive correlation was seen in the parietal cortex that was only significant for the autism group. Interestingly, in an exploratory analysis, we found sex differences in the relationships between cortical thickness and GABAA R BPND , and cortical thickness and AQ scores in the left postcentral gyrus. LAY SUMMARY: The thickness of the brain cortex and the density of the receptors associated with inhibitory neurotransmitter GABA have been hypothesized to underlie the neurobiology of autism. In this study, we found that these biomarkers correlate positively in the parietal cortex, but negatively in the frontal and occipital cortical regions of the brain. Furthermore, we collected preliminary evidence that the correlations between cortical thickness and GABA receptor density are sexdependent in a brain region where sensory inputs are registered.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Adulto , Trastorno Autístico/diagnóstico por imagen , Trastorno Autístico/patología , Encéfalo/patología , Mapeo Encefálico/métodos , Femenino , Humanos , Imagen por Resonancia Magnética/métodos , Masculino , Ácido gamma-AminobutíricoRESUMEN
Alterations in sensorimotor functions are common in individuals with autism spectrum disorder (ASD). Such aberrations suggest the involvement of the thalamus due to its key role in modulating sensorimotor signaling in the cortex. Although previous research has linked atypical thalamocortical connectivity with ASD, investigations of this association in high-functioning adults with autism spectrum disorder (HFASD) are lacking. Here, for the first time, we investigated the resting-state functional connectivity of the thalamus, medial prefrontal, posterior cingulate, and left dorsolateral prefrontal cortices and its association with symptom severity in two matched cohorts of HFASD. The principal cohort consisted of 23 HFASD (mean[SD] 27.1[8.9] years, 39.1% female) and 20 age- and sex-matched typically developing controls (25.1[7.2] years, 30.0% female). The secondary cohort was a subset of the ABIDE database consisting of 58 HFASD (25.4[7.8] years, 37.9% female) and 51 typically developing controls (24.4[6.7] years, 39.2% female). Using seed-based connectivity analysis, between-group differences were revealed as hyperconnectivity in HFASD in the principal cohort between the right thalamus and bilateral precentral/postcentral gyri and between the right thalamus and the right superior parietal lobule. The former was associated with autism-spectrum quotient in a sex-specific manner, and was further validated in the secondary ABIDE cohort. Altogether, we present converging evidence for thalamocortical hyperconnectivity in HFASD that is associated with symptom severity. Our results fill an important knowledge gap regarding atypical thalamocortical connectivity in HFASD, previously only reported in younger cohorts.