Imbalance of laminar-specific excitatory and inhibitory circuits of the orbitofrontal cortex in autism

Abstract

Background The human orbitofrontal cortex (OFC) is involved in assessing the emotional significance of events and stimuli, emotion-based learning, allocation of attentional resources, and social cognition. Little is known about the structure, connectivity and excitatory/inhibitory circuit interactions underlying these diverse functions in human OFC, as well as how the circuit is disrupted in individuals with autism spectrum disorder (ASD). Methods We used post-mortem brain tissue from neurotypical adults and individuals with ASD. We examined the morphology and distribution of myelinated axons across cortical layers in OFC, at the single axon level, as a proxy of excitatory pathways. In the same regions, we also examined the laminar distribution of all neurons and neurochemically- and functionally-distinct inhibitory neurons that express the calcium-binding proteins parvalbumin (PV), calbindin (CB), and calretinin (CR). Results We found that the density of myelinated axons increased consistently towards layer 6, while the average axon diameter did not change significantly across layers in both groups. However, both the density and diameter of myelinated axons were significantly lower in the ASD group compared with the Control group. The distribution pattern and density of the three major types of inhibitory neurons was comparable between groups, but there was a significant reduction in the density of excitatory neurons across OFC layers in ASD. Limitations This study is limited by the availability of human post-mortem tissue optimally processed for high-resolution microscopy and immunolabeling, especially from individuals with ASD. Conclusions The balance between excitation and inhibition in OFC is at the core of its function, assessing and integrating emotional and social cues with internal states and external inputs. Our preliminary results provide evidence for laminar-specific changes in the ratio of excitation/inhibition in OFC of adults with ASD, with an overall weakening and likely disorganization of excitatory signals and a relative strengthening of local inhibition. These changes likely underlie pathology of major OFC communications with limbic or other cortices and the amygdala in individuals with ASD, and may provide the anatomic basis for disrupted transmission of signals for social interactions and emotions in autism.

Ultrahigh field in vivo characterization of microstructural abnormalities in the orbitofrontal cortex and amygdala in autism

“…Anatomical studies of OFC in ASD (reviewed in Rolls & Grabenhorst, 2008) have revealed abnormalities its size and structure, and more recently, Liu et al (Liu et al, 2020) have reported post-mortem histological abnormalities in the right OFC of adult ASD individuals, with laminar-specific abnormalities of inhibitory neurons distribution.…”

“…Anatomical studies of the orbitofrontal cortex (OFC) in ASD (reviewed in Liu et al, 2020) have revealed abnormalities in the size and the structure of the OFC, together with differences in the subcortical white matter (WM) in this region, and more recently, Liu et al (2020) have reported post-mortem histological abnormalities in the right OFC of adult ASD individuals, with laminarspecific abnormalities of the density and the diameter of myelinated axons in that specific area.…”

Alteration of the Early Development Environment by Maternal Diet and the Occurrence of Autistic-like Phenotypes in Rat Offspring

“…Increased neuron numbers within the PFCx are noted in children with ASD [17]. Moreover, disturbed cortical excitation-inhibition balance is considered to be one of the pathophysiological mechanisms of ASD [60][61][62]. TAOK2 belongs to the MAP kinase kinase kinase (MAP3K) family, which regulates the p38 MAPK, SAPK/JNK and Hippo signaling pathways [63].…”

Altered Processing of Social Emotions in Individuals With Autistic Traits

“…ASD is commonly characterized by functional deficits in social behavior, difficulties in social communication, and restricted and repetitive interests (American Psychiatric Association, 2013). Such social impairment is a defining phenotypic feature of ASD (Ogawa et al, 2019;Liu et al, 2020). Previous studies of individuals with ASD have found diminished motivation to engage in social activities (Tsurugizawa et al, 2020), deficits in reciprocal social communication (De Crescenzo et al, 2019), and deficits in the ability to understand the beliefs and intentions of others (Chevallier et al, 2012;Ruta et al, 2017).…”