Functional impairments or trafficking defects of inhibitory glycine receptors (GlyRs) have been linked to human hyperekplexia/startle disease and autism spectrum disorders. We found that a lack of synaptic integration of GlyRs, together with disrupted receptor function, is responsible for a lethal startle phenotype in a novel spontaneous mouse mutant shaky, caused by a missense mutation, Q177K, located in the extracellular β8–β9 loop of the GlyR α1 subunit. Recently, structural data provided evidence that the flexibility of the β8–β9 loop is crucial for conformational transitions during opening and closing of the ion channel and represents a novel allosteric binding site in Cys-loop receptors. We identified the underlying neuropathological mechanisms in male and female shaky mice through a combination of protein biochemistry, immunocytochemistry, and both in vivo and in vitro electrophysiology. Increased expression of the mutant GlyR α1Q177K subunit in vivo was not sufficient to compensate for a decrease in synaptic integration of α1Q177Kβ GlyRs. The remaining synaptic heteromeric α1Q177Kβ GlyRs had decreased current amplitudes with significantly faster decay times. This functional disruption reveals an important role for the GlyR α1 subunit β8–β9 loop in initiating rearrangements within the extracellular–transmembrane GlyR interface and that this structural element is vital for inhibitory GlyR function, signaling, and synaptic clustering.SIGNIFICANCE STATEMENT GlyR dysfunction underlies neuromotor deficits in startle disease and autism spectrum disorders. We describe an extracellular GlyR α1 subunit mutation (Q177K) in a novel mouse startle disease mutant shaky. Structural data suggest that during signal transduction, large transitions of the β8–β9 loop occur in response to neurotransmitter binding. Disruption of the β8–β9 loop by the Q177K mutation results in a disruption of hydrogen bonds between Q177 and the ligand-binding residue R65. Functionally, the Q177K change resulted in decreased current amplitudes, altered desensitization decay time constants, and reduced GlyR clustering and synaptic strength. The GlyR β8–β9 loop is therefore an essential regulator of conformational rearrangements during ion channel opening and closing.

IntroductionPositive social interactions (PSIs) and stable relationships can exert substantial benefits on health. However, patients suffering from depression benefit less from these health-promoting effects. Moreover, relationship quality and even partners’ health has been found to be negatively affected by depressive symptomatology, which may result in overall impairments in social functioning of a romantic couple. Psychobiological research indicates that these impairments may be accompanied by a maladaptive regulation of the patient’s neuroendocrine response to external stressors. Concerning the improvement of social functioning, first studies showed promising results of “Cognitively Based Compassion Training (CBCT®)”. However, randomised trials are still scarce. Previous programmes did not involve participation of the patient’s romantic partner. Therefore, the present study aims to investigate whether a CBCT® programme adapted for couples (CBCT®-fC) can improve depressive symptoms, distress, social interaction skills and the neurobiological regulation of stress.Methods and analysisCouples with the female partner suffering from depression will be invited to participate in a pre-to-post intervention assessment on two consecutive days, respectively, involving a standardised PSI task, eye-tracking, ECG recordings, saliva-sampling, blood-sampling and questionnaire data. After baseline assessment, participating couples will be randomised to either a 10 week CBCT®-fC or to a treatment as usual control condition. The primary endpoint is the reduction of depressive symptoms measured by the Hamilton Depression Rating Scale. Secondary outcomes encompass self-rated depression (Beck Depression Inventory), attention towards the partners face during PSI (eye tracking), stress-related biomarkers (cortisol, α-amylase, interleukin (IL)-1ß/IL-6, heart rate variability), methylation of oxytocin-receptor-genes and serotonin-transporter-genes and self-ratings of psychological constructs such as relationship quality and empathy.Ethics and disseminationEthical approval has been obtained by the Ethics Committee of the Medical Faculty Heidelberg. Results will be presented in international, peer-reviewed journals and on conferences in the field of clinical psychology and psychiatry.Trial registration number NCT03080025.

Background: Depressive disorders are associated with attentional bias and social anhedonia. There is evidence supporting the hypothesis that depressed individuals participate less in potentially rewarding social situations and exhibit alterations in stress reactivity. With the present study, we aimed at investigating the affective and psychobiological response of couples with a depressed (female) partner in an instructed partnership appreciation task (PAT) that included positive and appreciative communication. Methods: In a quasi-experimental repeated-measures design, depressive couples (DCs)i.e., the female partner being diagnosed with a depressive disorder-were compared to non-depressive couples (NDCs). Study outcomes were the PAT-induced changes in state mood, momentary relationship satisfaction, salivary cortisol, and salivary alpha-amylase. Additionally, we assessed psychometric baseline data on depression, relationship quality, social support, and chronic stress. Data was analyzed using multilevel modeling. Results: A total of 184 individuals from N = 47 DCs and N = 45 NDCs were included. DCs were characterized by higher depressiveness, lower relationship quality, less actually received social support from the partner, and higher chronic stress than NDCs. Manipulation checks led to the additional exclusion of two couples. Regarding mood, depressed women showed lower baseline scores and no significant differences in mood increase compared to non-depressed women (p = 0.107). Increases in relationship satisfaction were significantly stronger in the depressed group (p = 0.035). In addition, we found a significantly stronger cortisol increase in depressed women, but only if relationship duration was taken into account as a moderating factor (p = 0.022). No significant group differences were found for women's amylase trajectories or for sexdependent interaction effects on the couple level (all p > 0.05).

Contactin-associated protein-like 2 (Caspr2) is a neurexin-like protein that has been associated with numerous neurological conditions. However, the specific functional roles that Caspr2 plays in the central nervous system and their underlying mechanisms remain incompletely understood. Here, we report on a functional role for Caspr2 in the developing cerebellum. Using a combination of confocal microscopy, biochemical analyses and behavioral testing, we show that loss of Caspr2 in the Cntnap2-/- knockout mouse results in impaired Purkinje cell dendritic development, altered intracellular signaling and motor coordination deficits. We also find that Caspr2 is highly enriched at synaptic specializations in the cerebellum. Using a proteomics approach, we identify type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) as a specific synaptic interaction partner of the Caspr2 extracellular domain (ECD) in the molecular layer (ML) of the developing cerebellum. The interaction of Caspr2 ECD with IP3R1 inhibits IP3R1-mediated changes in cellular morphology. Together, our work defines a mechanism by which Caspr2 controls the development and function of the cerebellum, and advances our understanding of how Caspr2 dysfunction might lead to specific brain disorders.

Over the past decades, mindfulness‐based interventions have been shown to improve individual health and well‐being in clinical and nonclinical settings. More recently, secular contemplative trainings were adapted to the couple context as research showed satisfying couple relationships to be one of the strongest predictors of physical and mental health. Mindfulness‐based interventions hence seem to be a promising treatment in couple counseling and therapy in both clinical and nonclinical settings. Therefore, we conducted a systematic review to provide an overview of the emerging literature in the field of mindfulness‐based interventions for couples and other dyads. Overall, sixteen studies met the inclusion criteria. To summarize the heterogeneous quantitative literature regarding individual outcomes, mindfulness interventions for couples seem to increase mindfulness, self‐compassion, well‐being, and quality of life. Additionally, we found initial evidence of beneficial effects on relieving psychopathological symptoms and psychobiological stress measures. Measures of relationship quality were the predominant dyadic outcome. Based on these studies, we cautiously conclude that mindfulness trainings can enhance relationship quality. Practitioners should be aware that mindfulness‐based interventions for couples can potentially improve the perceived relationship quality between partners and the individual burden. Future studies should expand the field, particularly with regard to other contemplative practices for couples such as compassion interventions.

Depression occurs in an interpersonal dynamic and living with a depressed person can lead to a significant burden on the partner. Instruments measuring burden do not address couples and often measure caregiving for individuals with schizophrenic disorders. The partner burden in depression (PBD) questionnaire is a new instrument measuring PBD by asking individuals,(1) which symptoms they can observe in their depressed partners and (2) to which degree this burdens them.Hence, PBD combines measuring the awareness of observed depressive symptoms and the resulting burden. Additionally, it addresses aspects unique to couple relationships. Our German validation confirmed a one-factor model with 12 items. The PBD had good psychometric properties and was sensitive to change. Partner burden predicted self-reported depressive symptoms (PHQ-9) over time. PBD is short, easily applicable in research and

Psychomotor dysfunction (PMD) is a core element and key contributor to disability in late life depression (LLD), which responds well to electroconvulsive therapy (ECT). The neurobiology of PMD and its response to ECT are not well understood. We hypothesized that PMD in LLD is associated with lower striatal volume, and that striatal volume increase following ECT explains PMD improvement. We analyzed data from a two-center prospective cohort study of 110 LLD subjects (>55 years) receiving ECT. Brain MRI and assessment of mood, cognition, and PMD was performed 1 week before, 1 week after, and 6 months after ECT. Volumetry of the caudate nucleus, putamen, globus pallidus, and nucleus accumbens was derived from automatically segmented brain MRIs using Freesurfer®. Linear multiple regression analyses were used to study associations between basal ganglia volume and PMD. Brain MRI was available for 66 patients 1 week post ECT and in 22 patients also six months post ECT. Baseline PMD was associated with a smaller left caudate nucleus. One week after ECT, PMD improved and volume increases were detected bilaterally in the caudate nucleus and putamen, and in the right nucleus accumbens. Improved PMD after ECT did not relate to the significant volume increases in these structures, but was predicted by a nonsignificant volume change in the right globus pallidus. No volume differences were detected 6 months after ECT, compared to baseline. Although PMD is related to lower striatal volume in LLD, ECT-induced increase of striatal volume does not explain PMD improvement.

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