Biobehavioral correlates of an fMRI index of striatal tissue iron in depressed patients.

Dopaminergic function is a critical transdiagnostic neurophysiological dimension with broad relevance in psychiatry. Normalized T2*-weighted (nT2*w) imaging has been previously investigated as a method to quantify biological properties of tissue in the striatum (e.g., tissue iron), providing a widely available, in vivo marker with potential relevance to dopaminergic function; but no prior study to our knowledge has examined this neuroimaging marker in clinical depression. In a treatment-seeking, clinically depressed sample (n = 110), we quantified tissue iron (nT2*w) in striatal regions. We assessed test-retest reliability and correlated values with dimensional features across levels of analysis, including demographic/biological (sex, age, Body Mass Index), neuroanatomical (hippocampal atrophy, which was quantified using a recently validated machine-learning algorithm), and performance-based (Affective Go/NoGo task performance) indices with relevance to depressive neurocognition. Across patients, decreased tissue iron concentration (as indexed by higher nT2*w) in striatal regions correlated with indices of decreased cognitive-affective function on the Affective Go/NoGo task. Greater caudate nT2*w also correlated with greater hippocampal atrophy. Striatal tissue iron concentrations were robustly lower in female patients than males but gender differences did not explain relations with other neurocognitive variables. A widely available fMRI index of striatal tissue properties, which exhibited strong psychometric properties and can be readily quantified from most fMRI datasets irrespective of study-specific features such as task design, showed relevance to multiple biobehavioral markers of pathophysiology in the context of moderate-to-severe, treatment-resistant depression. Striatal tissue iron may play a role in dimensional and subgroup-specific features of depression, with implications for future research on depression heterogeneity.

Identification of a binding site for ganglioside on the receptor binding domain of tetanus toxin.

The carboxyl-terminal region of the tetanus toxin heavy chain (H(C) fragment) binds to di- and trisialylgangliosides on neuronal cell membranes. To determine which amino acids in tetanus toxin are involved in ganglioside binding, homology modeling was performed using recently resolved X-ray crystallographic structures of the tetanus toxin H(C) fragment. On the basis of these analyses, two regions in tetanus toxin that are structurally homologous with the binding domains of other sialic acid and galactose-binding proteins were targeted for mutagenesis. Specific amino acids within these regions were altered using site-directed mutagenesis. The amino acid residue tryptophan 1288 was found to be critical for binding of the H(C) fragment to ganglioside GT1b. Docking of GD1b within this region of the toxin suggested that histidine 1270 and aspartate 1221 were within hydrogen bonding distance of the ganglioside. These two residues were mutagenized and found also to be important for the binding of the tetanus toxin H(C) fragment to ganglioside GT1b. In addition, the H(C) fragments mutagenized at these residues have reduced levels of binding to neurites of differentiated PC-12 cells. These studies indicate that the amino acids tryptophan 1288, histidine 1270, and aspartate 1221 are components of the GT1b binding site on the tetanus toxin H(C) fragment.