The cognitive phenotype of autism has been correlated with an altered balance of excitation to inhibition in the cerebral cortex, which could result from a change in the number, function, or morphology of GABA-expressing interneurons. The number of GABAergic interneuron subtypes has not been quantified in the autistic cerebral cortex. We classified interneurons into 3 subpopulations based on expression of the calcium-binding proteins parvalbumin, calbindin, or calretinin. We quantified the number of each interneuron subtype in postmortem neocortical tissue from 11 autistic cases and 10 control cases. Prefrontal Brodmann Areas (BA) BA46, BA47, and BA9 in autism and age-matched controls were analyzed by blinded researchers. We show that the number of parvalbumin+ interneurons in these 3 cortical areas-BA46, BA47, and BA9-is significantly reduced in autism compared with controls. The number of calbindin+ and calretinin+ interneurons did not differ in the cortical areas examined. Parvalbumin+ interneurons are fast-spiking cells that synchronize the activity of pyramidal cells through perisomatic and axo-axonic inhibition. The reduced number of parvalbumin+ interneurons could disrupt the balance of excitation/inhibition and alter gamma wave oscillations in the cerebral cortex of autistic subjects. These data will allow development of novel treatments specifically targeting parvalbumin interneurons.

The observed behavioral deficits, especially regarding social behaviors, strengthens the face validity of the gabrb3 gene deficient mouse as being a model of autism spectrum disorder.

The title and the penultimate paragraph of the Discussion section incorrectly referred to the "medial prefrontal cortex." The word "medial" should not have appeared. This has been corrected in the article online.

Autism spectrum disorder (ASD) is diagnosed based on three core features: impaired social interactions, deficits in communication and repetitive or restricted behavioral patterns. Against this backdrop, abnormal sensory processing receives little attention despite its prevalence and the impact it exerts on the core diagnostic features. Understanding the source of these sensory abnormalities is paramount to developing intervention strategies aimed at maximizing the coping ability of those with ASD. Consequently, we chose to examine whether sensory abnormalities were present in mice heterozygous for the Gabrb3 gene, a gene strongly associated with ASD. Mice were assessed for tactile and heat sensitivity, sensorimotor competence (accelerating rotarod task) and sensorimotor gating by prepulse inhibition of the acoustic startle reflex (PPI). All heterozygotes exhibited an increase in seizure susceptibility and similar reductions in Gabrb3 expression in the dorsal root ganglia, spinal cord, whole brain and amygdala. Interestingly, significant differences were noted between heterozygous variants in regards to tactile sensitivity, heat sensitivity, sensorimotor competence and PPI along with differences in Gabrb3 expression in the reticular thalamic nucleus and the bed nucleus of stria terminalis. These differences were influenced by the heterozygotes’ gender and whether the Gabrb3 gene was of paternal or maternal origin. These results are not adequately explained by simple haploinsufficiency of Gabrb3, therefore, additional mechanisms are likely to be involved. In addition, this is the first report of the occurrence of tactile and heat hypersensitivity in an ASD mouse model, two features often associated with ASD.

We report quantitative label-free imaging with phase and polarization (QLIPP) for simultaneous measurement of density, anisotropy, and orientation in unlabeled live cells and tissue slices. We combine QLIPP with deep neural networks to predict fluorescence images of diverse cell and tissue structures. QLIPP images reveal anatomical regions and axon tract orientation in prenatal human brain tissue sections that are not visible using brightfield imaging. We report a variant of UNet architecture, multi-channel 2.5D U-Net, for computationally efficient prediction of fluorescence images in three dimensions and over large fields of view. Further, we develop data normalization methods for accurate prediction of myelin distribution over large brain regions. We show that experimental defects in labeling the human tissue can be rescued with quantitative label-free imaging and neural network model. We anticipate that the proposed method will enable new studies of architectural order at spatial scales ranging from organelles to tissue.

An interneuron alteration has been proposed as a source for the modified balance of excitation / inhibition in the cerebral cortex in autism. We previously demonstrated a decreased number of parvalbumin (PV)-expressing interneurons in prefrontal cortex in autism. PV-expressing interneurons include chandelier (Ch) and basket (Bsk) cells. We asked whether the decreased PV+ interneurons affected both Ch cells and Bsk cells in autism. The lack of single markers to specifically label Ch cells or Bsk cells presented an obstacle for addressing this question. We devised a method to discern between PV-Ch and PV-Bsk cells based on the differential expression of Vicia villosa lectin (VVA). VVA binds to N-acetylgalactosamine, that is present in the perineuronal net surrounding some cell types where it plays a role in intercellular communication. N-acetylgalactosamine is present in the perineuronal net surrounding Bsk but not Ch cells. We found that the number of Ch cells is consistently decreased in the prefrontal cortex of autistic (n = 10) when compared with control (n = 10) cases, while the number of Bsk cells is not as severely affected. This finding expand our understanding of GABAergic system functioning in the human cerebral cortex in autism, which will impact translational research directed towards providing better treatment paradigms for individuals with autism.

BackgroundThe aim of the present study was to describe the activity of a set of opioid drugs, including partial agonists, in a human embryonic kidney cell system stably expressing only the mouse κ-opioid receptors. Receptor activation was assessed by measuring the inhibition of cyclic adenosine mono phosphate (cAMP) production stimulated by 5 μM forskolin. Intrinsic activities and potencies of these ligands were determined relative to the endogenous ligand dynorphin and the κ agonist with the highest intrinsic activity that was identified in this study, fentanyl.ResultsAmong the ligands studied naltrexone, WIN 44,441 and dezocine, were classified as antagonists, while the remaining ligands were agonists. Intrinsic activity of agonists was assessed by determining the extent of inhibition of forskolin-stimulated cAMP production. The absolute levels of inhibition of cAMP production by each ligand was used to describe the rank order of intrinsic activity of the agonists; fentanyl = lofentanil ≥ hydromorphone = morphine = nalorphine ≥ etorphine ≥ xorphanol ≥ metazocine ≥ SKF 10047 = cyclazocine ≥ butorphanol > nalbuphine. The rank order of affinity of these ligands was; cyclazocine > naltrexone ≥ SKF 10047 ≥ xorphanol ≥ WIN 44,441 > nalorphine > butorphanol > nalbuphine ≥ lofentanil > dezocine ≥ metazocine ≥ morphine > hydromorphone > fentanyl.ConclusionThese results elucidate the relative activities of a set of opioid ligands at κ-opioid receptor and can serve as the initial step in a systematic study leading to understanding of the mode of action of these opioid ligands at this receptor.

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