Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (mis_TMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (mis_ATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10⁻⁶) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where mis_TMD+Linker predominantly led to NMDAR gain-of-function, while mis_ATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a^+/− cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and mis_ATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of mis_TMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders.

People with schizophrenia have difficulties in interpreting social information. Much social information is gathered from faces, and face processing represents a well-characterized model to study the basis of social deficits in schizophrenia. A narrative review of selected literature. Individuals with schizophrenia have impairments in recognizing basic emotions and making social judgements from facial stimuli. The neural basis of these abnormalities is still being determined. However, initial evidence implicates dysfunction of frontal and temporal lobe brain regions. Hyper-activation of the amygdala, a brain region involved in fear, to facial stimuli may be an important underlying neural abnormality. The present article highlights the difficulties that people with schizophrenia have in interpreting social cues from faces. Research is required to understand more about both the basis of social deficits in schizophrenia and their potential remediation.

HIV/AIDS is associated with significant mental health morbidity in high-income countries, and depression associated with HIV/AIDS has been linked with faster disease progression and reduced drug adherence. However, research on mental health is scarce in sub-Saharan Africa where infection levels are highest. This cross-sectional study of 220 HIV-positive outpatients at a dedicated Tanzanian HIV/AIDS care centre assessed sociodemographics, clinical variables and prevalence of ICD-10 common mental health diagnoses via a standardised psychiatric questionnaire (the Clinical Interview Schedule – Revised). Depression or mixed anxiety and depression was identified in 15.5% of subjects, with 4.5% suffering from other anxiety disorders. This suggests routine HIV care in sub-Saharan Africa should include assessment and treatment of mental health issues.

Systematic assessment of the prevalence and pattern of liver function test (LFT) abnormalities associated with regular antipsychotics in adult humans and consideration of management of such abnormalities. Systematic search identifying cohort, cross-sectional or case studies/series, reporting LFT abnormalities in patients receiving regular antipsychotics. EMBASE, PsychINFO, and MEDLINE were searched for studies in English from record onset. Abstracts were independently screened for eligibility by 2 researchers. Ineligible studies included those that did not report LFT reference ranges, those that studied fewer than 10 patients on a given antipsychotic, and those studying children. Key variables in group studies were extracted. Case studies/series were examined for patient outcome. Ten group studies and 91 case studies/series were eligible, although quality was poor. All groups receiving regular antipsychotics had a prevalence of LFT abnormalities greater than chance. The median percentage of patients with any abnormal LFT on any antipsychotic was 32%, with a range of 5% to 78%. The median percentage of patients with clinically significant elevations was 4%, with a range of 0% to 15%. Transaminases were most commonly elevated. Abnormalities were generally asymptomatic, arose within 6 weeks, and were either stably persistent or resolved with continued treatment. Case reports suggested that antipsychotics can be associated with severe hepatitis, fatal in a small minority of cases. Chlorpromazine is most commonly associated with acute liver injury. The LFT abnormalities in patients receiving regular antipsychotics are common but generally mild and transient. Very rarely, a severe or fatal hepatic injury can emerge.

Aberrant NMDA receptor (NMDAR) activity contributes to several neurological disorders, but direct antagonism is poorly tolerated therapeutically. The GluN2B cytoplasmic C-terminal domain (CTD) represents an alternative therapeutic target since it potentiates excitotoxic signaling. The key GluN2B CTD-centred event in excitotoxicity is proposed to involve its phosphorylation at Ser-1303 by Dapk1, that is blocked by a neuroprotective cell-permeable peptide mimetic of the region. Contrary to this model, we find that excitotoxicity can proceed without increased Ser-1303 phosphorylation, and is unaffected by Dapk1 deficiency in vitro or following ischemia in vivo. Pharmacological analysis of the aforementioned neuroprotective peptide revealed that it acts in a sequence-independent manner as an open-channel NMDAR antagonist at or near the Mg²⁺ site, due to its high net positive charge. Thus, GluN2B-driven excitotoxic signaling can proceed independently of Dapk1 or altered Ser-1303 phosphorylation.

Background: The hippocampus plays a central role in memory formation. There is considerable evidence of abnormalities in hippocampal structure and function in schizophrenia, which may differentiate it from bipolar disorder. However, no previous studies have compared hippocampal activation in schizophrenia and bipolar disorder directly.Method: Fifteen patients with schizophrenia, 14 patients with bipolar disorder and 14 healthy comparison subjects took part in the study. Subjects performed a face–name pair memory task during functional magnetic resonance imaging (fMRI). Differences in blood oxygen level-dependent (BOLD) activity were determined during encoding and retrieval of the face–name pairs.Results: The patient groups showed significant differences in hippocampal and prefrontal cortex (PFC) activation during face–name pair learning. During encoding, patients with schizophrenia showed decreased anterior hippocampal activation relative to subjects with bipolar disorder, whereas patients with bipolar disorder showed decreased dorsal PFC activation relative to patients with schizophrenia. During retrieval, patients with schizophrenia showed greater activation of the dorsal PFC than patients with bipolar disorder. Patients with schizophrenia also differed from healthy control subjects in the activation of several brain regions, showing impaired superior temporal cortex activation during encoding and greater dorsal PFC activation during retrieval. These effects were evident despite matched task performance.Conclusions: Patients with schizophrenia showed deficits in hippocampal activation during a memory task relative to patients with bipolar disorder. The disorders were further distinguished by differences in PFC activation. The results demonstrate that these disorders can distinguished at a group level using non-invasive neuroimaging.