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Autism spectrum disorder (ASD) is associated with neurodevelopmental alterations, including atypical forebrain cellular organization. Mutations in several ASD-related genes often result in cerebral cortical anomalies, such as the abnormal developmental migration of excitatory pyramidal cells and the malformation of inhibitory neuronal circuitry. Notably here, mutations in the CNTNAP2 gene result in ectopic superficial cortical neurons stalled in lower cortical layers and alterations to the balance of cortical excitation and inhibition. However, the broader circuit-level implications of these findings have not been previously investigated. Therefore, we assessed whether ectopic cortical neurons in CNTNAP2 mutant mice form aberrant connections with higher-order thalamic nuclei, potentially accounting for some autistic behaviors, such as repetitive and hyperactive behaviors. Furthermore, we assessed whether the development of parvalbumin-positive (PV) cortical interneurons and their specialized matrix support structures, called perineuronal nets (PNNs), were altered in these mutant mice. We found alterations in both ectopic neuronal connectivity and in the development of PNNs, PV neurons and PNNs enwrapping PV neurons in various sensory cortical regions and at different postnatal ages in the CNTNAP2 mutant mice, which likely lead to some of the cortical excitation/inhibition (E/I) imbalance associated with ASD. These findings suggest neuroanatomical alterations in cortical regions that underlie the emergence of ASD-related behaviors in this mouse model of the disorder.
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The Reversal Characteristics of GABAergic Neurons: A Neurovascular Model
Neurovascular coupling (NVC) is the ability to locally adjust vascular resistance as a function of neuronal activity. Recent experiments have illustrated that NVC is partially independent of metabolic signals. In addition Nitric Oxide (NO) has been shown in some instances to provide an important mechanism in altering vascular resistance. An extension to the original model of NVC [1] has been developed to include the activation of both somato-sensory neurons and GABAergic interneurons and to investigate the role of NO and the delicate balance of GABA and neuronal peptide enzymes (NPY) pathways. The numerical model is compared to murine experimental data that provides time-dependent profiles of oxy, de-oxy and total-haemoglobin. The results indicate a delicate balance that exists between GABA and NPY when n-NOS interneurons are activated mediated by NO. Whereas somato-sensory neurons (producing potassium into the extracellular space) do not seem to be effected by the inhibition of NO. Further work will need to be done to investigate the role of NO when stimulation periods are increased substantiallyfrom the short pulses of 2 seconds as used in the above experiments.
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- Award ID(s):
- 1953271
- PAR ID:
- 10557008
- Publisher / Repository:
- American Society of Mechanical Engineers
- Date Published:
- Journal Name:
- Journal of biomechanical engineering
- ISSN:
- 0148-0731
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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