Habit learning, action selection and performance are modulated by the basal ganglia, a collection of groups of neurons located below the cerebral cortex in the brain. In autism, there is emerging evidence that parts of the basal ganglia are structurally and functionally altered disrupting normal information flow. The basal ganglia through its interconnected circuits with the cerebral cortex and the cerebellum can potentially impact various motor and cognitive functions in the autism brain.
As selective serotonin reuptake inhibitors (SSRIs) are among the most commonly prescribed medications in autism, we aimed to determine whether targets for SSRIs are differentially affected in three cortical areas in children and adults with autism compared to neurotypical individuals. Utilizing a large cohort of postmortem brain tissue (n = 14–19 per group), saturation ligand binding assays were conducted on sections from the anterior cingulate cortex (ACC), posterior cingulate cortex, and fusiform gyrus (FG). Specific binding to the 5‐HT transporter (5‐HTT) as well as to 5‐HT2 and 1A receptors (5‐HT₂, 5‐HT1A) was quantified in superficial and deep layers of each region using the ligands [3H]‐citalopram (5‐HTT), [3H]‐ketanserin (5‐HT2), and [3H]‐8‐OH‐DPAT (5‐HT1A). A Welch’s t‐test was utilized to compare receptor densities (B
max), revealing a statistically significant decrease in 5‐HTT within the ACC of the entire autism cohort. There was also a decrease in 5‐HT2 receptor density in the ACC in the adult cohort, but not in child postmortem autism cases as compared to controls. Comparing linear regression lines of B
max values plotted against age, shows a significantly lower intercept for 5‐HTT in autism (p = 0.025). 5‐HT₂ density increases with age in control cases, whereas in autism there is a decrease with age and significantly different slopes between regression lines (p = 0.032). This suggests a deficit in 5‐HTT within the ACC in individuals with autism, while decreases in 5‐HT₂ density are age‐dependent. There were no differences in receptor densities in the posterior cingulate cortex or FG in autism and no differences in ligand affinity (K
D) across all regions and ligands examined.
In the-present study we describe the antagonistic effects of the covalently dimerized insulin derivative B29,B29'-suberoyl-insulin on insulin receptors in 3T3-L1 mouse cells. In differentiated 3T3-L1 adipocytes, the derivative fully inhibits binding of '2I-labeled insulin to its receptor with about the same affinity as unlabeled insulin. In contrast, the dimerized derivative only partially (approximately 20%) mimics insulin's effects on glucose transport and DNA synthesis in the absence of insulin. In the presence of insulin, the agent competitively inhibits insulin-stimulated DNA synthesis ([3HJthymidine incorporation into total DNA), glucose transport activity (2-deoxyglucose uptake rate), and insulin receptor tyrosine kinase activity. In rat adipocytes, in contrast, the dimerized derivative stimulates glucose transport (initial 3-O-methylglucose as well as 2-deoxyglucose uptake rates) to the same extent as insulin does, and it fails to inhibit the effect of insulin. The data indicate that the dimerized insulin derivative B29,B29'-suberoyl-insulin is an insulin receptor antagonist (partial agonist) which retains a moderate intrinsic activity. The effects of this agent reveal a striking difference in insulin receptor-mediated stimulation of glucose transport between 3T3-L1 fatty fibroblasts and the mature rat adipocyte.A large number of insulin analogues from different species and synthetically modified derivatives have previously been tested for their biological activity (1). All derivatives investigated so far were pure agonists of the insulin receptor, since they differed only in potency (concentration eliciting halfmaximal effects, EC50) but produced identical maximal responses in various bioassays. Accordingly, an excellent correlation between the binding affinity ofthe derivatives and their biological potency in the fat cell bioassay was observed. As a notable exception from this correlation, insulins from hagfish, porcupine, and coypu had lower biological activities than expected on the basis of their binding affinities (1).Further, dimerized insulin derivatives exhibited an even more striking discrepancy between binding affinity and biological potency (2). In IM9 lymphocytes, the covalently dimerized insulin derivative B29,B29'-suberoyl-insulin induced insulin receptor internalization to the same extent as insulin but failed to stimulate the receptor tyrosine kinase (3). In isolated adipocytes, the compound fully stimulated glucose transport but produced only 25% of the maximal effect of insulin on the receptor tyrosine kinase activity under conditions of full receptor occupancy (4, 5). These data prompted us to assume that dimerized insulin derivatives might antagonize some actions of insulin and might therefore be used to analyze diverse effects of the hormone. Thus, in the present study we investigated the effects of the covalent insulin dimer B29,B29'-suberoyl-insulin on DNA synthesis and glucose transport in 3T3-L1 adipocytes, initially aiming at a differentiation of the acute effects (met...
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