Identifying specific prefrontal neurons that contribute to autism-associated abnormalities in physiology and social behavior

Abstract

Functional imaging and gene expression studies both implicate the medial prefrontal cortex (mPFC), particularly deep-layer projection neurons, as a potential locus for autism pathology. Here, we explored how specific deep-layer prefrontal neurons contribute to abnormal physiology and behavior in mouse models of autism. First, we find that across three etiologically distinct models-in utero valproic acid (VPA) exposure, CNTNAP2 knockout and FMR1 knockout-layer 5 subcortically projecting (SC) neurons consistently exhibit reduced input resistance and action potential firing. To explore how altered SC neuron physiology might impact behavior, we took advantage of the fact that in deep layers of the mPFC, dopamine D2 receptors (D2Rs) are mainly expressed by SC neurons, and used D2-Cre mice to label D2R+ neurons for calcium imaging or optogenetics. We found that social exploration preferentially recruits mPFC D2R+ cells, but that this recruitment is attenuated in VPA-exposed mice. Stimulating mPFC D2R+ neurons disrupts normal social interaction. Conversely, inhibiting these cells enhances social behavior in VPA-exposed mice. Importantly, this effect was not reproduced by nonspecifically inhibiting mPFC neurons in VPA-exposed mice, or by inhibiting D2R+ neurons in wild-type mice. These findings suggest that multiple forms of autism may alter the physiology of specific deep-layer prefrontal neurons that project to subcortical targets. Furthermore, a highly overlapping population-prefrontal D2R+ neurons-plays an important role in both normal and abnormal social behavior, such that targeting these cells can elicit potentially therapeutic effects.

Rotenone exerts developmental neurotoxicity in a human brain spheroid model

“…In addition, other specific neuronal markers were altered, for instance, we observed up-regulation of SSTR2 at 2 weeks, up-regulation of OLFM1 at 4 and 8 weeks, and up-regulation of PDE1A at 8 weeks. Together with the down-regulation of CNTNAP2 , a neuronal gene involved in complex neurological disorders such as autism and schizophrenia (Brumback et al, 2017), the EGSEA results strongly supports the existence of multiple effects of rotenone on diverse neuronal populations present during the course of BrainSpheres maturation, with a more pronounced effect on dopaminergic neurons.…”

Impaired social contacts with familiar anesthetized conspecific in CA3‐restricted brain‐derived neurotrophic factor knockout mice

“…Given the evidence that the central pain systems may participate in the processing of and responding to social signals, the KO mice may have deficits in neuronal circuits that process both pain and social information. The anterior cingulate cortex (ACC) is one of such areas . Importantly, ACC has been implicated not only in pain sensitization and determining the affective state of self but in perceiving the state of others .…”

Behavioral Modulation by Social Experiences in Rodent Models

“…Instead, the social signals themselves act as reinforcers and it would be interesting to determine how they are encoded to become analogues of unconditional stimuli. Recent studies have identified neurons and molecules in the high brain structure that respond to social signals and modulate social behaviors (Brumback et al, 2017;Hung et al, 2017;Li et al, 2017;Nasanbuyan et al, 2017;Remedios et al, 2017;Yao, Bergan, Lanjuin, & Dulac, 2017). The next challenge would be to understand how those cells are recruited by social signals and what their effectors-targets are.…”