Abstract
BackgroundSensory processing deficits are common in individuals with neurodevelopmental disorders. One hypothesis is that deficits may be more detectable in downstream, “higher” sensory areas. A mouse model of Angelman syndrome (AS), which lacks expression of the maternally inherited Ube3a allele, has deficits in synaptic function and experience-dependent plasticity in the primary visual cortex. Thus, we hypothesized that AS model mice have deficits in visually driven neuronal responsiveness in downstream higher visual areas (HVAs).MethodsHere, we used intrinsic signal optical imaging and two-photon calcium imaging to map visually evoked neuronal activity in the primary visual cortex and HVAs in response to an array of stimuli.ResultsWe found a highly specific deficit in HVAs. Drifting gratings that changed speed caused a strong response in HVAs in wildtype mice, but this was not observed in littermate AS model mice. Further investigation with two-photon calcium imaging revealed the effect to be largely driven by aberrant responses of inhibitory interneurons, suggesting a cellular basis for higher level, stimulus-selective cortical dysfunction in AS.ConclusionAssaying downstream, or “higher” circuitry may provide a more sensitive measure for circuit dysfunction in mouse models of neurodevelopmental disorders.Trial registrationNot applicable.
Highlights
Copy number variants in the UBE3A gene, which encodes an E3 ubiquitin ligase, result in neurodevelopmental disorders in humans
We used in vivo intrinsic signal optical imaging (ISOI) to first map V1 and higher visual areas (HVAs) simultaneously, and to measure cortical responses to visual stimuli
An increase in inhibitory interneuron activity in both V1 and AL of WT mice outweighed the decrease in excitatory neuron activity during the same stimulus epoch to produce a net increase in neuronal activity (V1: t(2460) = 5.027, p < 0.0001, WT: 0.25 ± 0.01, Angelman syndrome (AS): 0.18 ± 0.007; AL: t(1174) = 4.296, p < 0.0001, WT: 0.042 ± 0.006, AS: 0.0064 ± 0.005). These results suggest that the activity modulation observed with ISOI in AL of WT mice arises from increases in inhibitory interneuron activity during the slow down” (SD) epoch of the stimulus, and the absence of activity modulation in AL of AS mice is due to a lack of inhibitory interneuron activity surge during the SD epoch of the stimulus
Summary
Copy number variants in the UBE3A gene, which encodes an E3 ubiquitin ligase, result in neurodevelopmental disorders in humans. Loss of maternal Ube3a does not alter retinotopic map formation in primary visual cortex (V1), eye-opening, or acuity development; but it does alter specific V1 microcircuits and impairs ocular dominance plasticity, a measure of the brain’s malleability to adapt to changes in the pattern of visual inputs [20,21,22,23]. These findings suggest that functional deficits in processing likely emerge with the developmental refinement of circuitry, but details of these deficits remain unknown. We hypothesized that AS model mice have deficits in visually driven neuronal responsiveness in downstream higher visual areas (HVAs)
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