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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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Behavioral regulation by perineuronal nets in the prefrontal cortex of the CNTNAP2 mouse model of autism spectrum disorder
Autism spectrum disorders (ASDs) arise from altered development of the central nervous system, and manifest behaviorally as social interaction deficits and restricted and repetitive behaviors. Alterations to parvalbumin (PV) expressing interneurons have been implicated in the neuropathological and behavioral deficits in autism. In addition, perineuronal nets (PNNs), specialized extracellular matrix structures that enwrap the PV-expressing neurons, also may be altered, which compromises neuronal function and susceptibility to oxidative stress. In particular, the prefrontal cortex (PFC), which regulates several core autistic traits, relies on the normal organization of PNNs and PV-expressing cells, as well as other neural circuit elements. Consequently, we investigated whether PNNs and PV-expressing cells were altered in the PFC of the CNTNAP2 knockout mouse model of ASD and whether these contributed to core autistic-like behaviors in this model system. We observed an overexpression of PNNs, PV-expressing cells, and PNNs enwrapping PV-expressing cells in adult CNTNAP2 mice. Transient digestion of PNNs from the prefrontal cortex (PFC) by injection of chondroitinase ABC in CNTNAP2 mutant mice rescued some of the social interaction deficits, but not the restricted and repetitive behaviors. These findings suggest that the neurobiological regulation of PNNs and PVs in the PFC contribute to social interaction behaviors in neurological disorders including autism.
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- Award ID(s):
- 1652432
- PAR ID:
- 10629697
- Publisher / Repository:
- Frontiers Media
- Date Published:
- Journal Name:
- Frontiers in Behavioral Neuroscience
- Volume:
- 17
- ISSN:
- 1662-5153
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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Fast-spiking parvalbumin (PV)-positive cells are key players in orchestrating pyramidal neuron activity and thus serve an indispensable role in cognitive function and emotional regulation. Feed-forward excitatory inputs, essential for the function of PV cells, are disrupted in various neurological conditions, including schizophrenia (SCZ). However, it is not clear how diseaseassociated stressors such as immune dysregulation contribute to defects in particular cell types or neuronal circuits. We have developed a novel transgenic mouse line that permits conditional, cell-type specific overexpression (OE) of the immune complement component 4 (C4) gene, which is highly associated with SCZ. Using this genetic approach, we demonstrate that specific global OE of mouse C4 (mC4) in PV cells causes pathological anxiety-like behavior in male, but not female mice. In the male medial prefrontal cortex (mPFC), this sexually dimorphic behavioral alteration was accompanied by a reduction in excitatory inputs to fast-spiking cells and an enhancement of their inhibitory connections. Additionally, in PV cells, elevated levels of mC4 led to contrasting effects on the excitability of cortical cells. In males, PV cells and pyramidal neurons exhibited reduced excitability, whereas in females, PV cells displayed heightened excitability. Contrary to the behavioral changes seen with elevated mC4 levels in PV cells, pan-neuronal overexpression did not increase anxiety-like behaviors. This indicates that mC4 dysfunction, particularly in fast-spiking cells, has a more significant negative impact on anxiety-like behavior than widespread alterations in the neuronal complement. Consequently, by employing a novel mouse model, we have demonstrated a causal relationship between the conditional overexpression of the schizophrenia risk gene C4 in fast-spiking neurons and the susceptibility of cortical circuits in male mice, resulting in changes in behaviors associated with prefrontal cortex function.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.3389/fnbeh.2023.1114789
