Pathogenic SYNGAP1 mutations impair cognitive development by disrupting maturation of dendritic spine synapses.

Mutations that cause intellectual disability (ID) and autism spectrum disorder (ASD) are commonly found in genes that encode for synaptic proteins. However, it remains unclear how mutations that disrupt synapse function impact intellectual ability. In the SYNGAP1 mouse model of ID/ASD, we found that dendritic spine synapses develop prematurely during the early postnatal period. Premature spine maturation dramatically enhanced excitability in the developing hippocampus, which corresponded with the emergence of behavioral abnormalities. Inducing SYNGAP1 mutations after critical developmental windows closed had minimal impact on spine synapse function, whereas repairing these pathogenic mutations in adulthood did not improve behavior and cognition. These data demonstrate that SynGAP protein acts as a critical developmental repressor of neural excitability that promotes the development of life-long cognitive abilities. We propose that the pace of dendritic spine synapse maturation in early life is a critical determinant of normal intellectual development.

Household income is associated with functional outcomes in a multi-institutional cohort of patients with ischemic stroke and COVID-19.

OBJECTIVES: The COVID-19 pandemic has heightened awareness of health disparities associated with socioeconomic status (SES) across the United States. We examined whether household income is associated with functional outcomes after stroke and COVID-19. MATERIALS AND METHODS: This was a multi-institutional, retrospective cohort study of consecutively hospitalized patients with SARS-CoV-2 and radiographically confirmed stroke presenting from March through November 2020 to any of five comprehensive stroke centers in metropolitan Chicago, Illinois, USA. Zip-code-derived household income was dichotomized at the Chicago median. Logistic regression was used to examine the relationship between household income and good functional outcome (modified Rankin Scale 0-3 at discharge, after ischemic stroke). RESULTS: Across five hospitals, 159 patients were included. Black patients comprised 48.1%, White patients 38.6%, and Hispanic patients 27.7%. Median household income was $46,938 [IQR: $32,460-63,219]. Ischemic stroke occurred in 115 (72.3%) patients (median NIHSS 7, IQR: 0.5-18.5) and hemorrhagic stroke in 37 (23.7%). When controlling for age, sex, severe COVID-19, and NIHSS, patients with ischemic stroke and household income above the Chicago median were more likely to have a good functional outcome at discharge (OR 7.53, 95% CI 1.61 - 45.73; P=0.016). Race/ethnicity were not included in final adjusted models given collinearity with income. CONCLUSIONS: In this multi-institutional study of hospitalized patients with stroke, those residing in higher SES zip codes were more likely to have better functional outcomes, despite controlling for stroke severity and COVID-19 severity. This suggests that area-based SES factors may play a role in outcomes from stroke and COVID-19.

NudC regulates photoreceptor disk morphogenesis and rhodopsin localization.

The outer segment (OS) of rod photoreceptors consist of a highly modified primary cilium containing phototransduction machinery necessary for light detection. The delivery and organization of the phototransduction components within and along the cilium into the series of stacked, highly organized disks is critical for cell function and viability. How disks are formed within the cilium remains an area of active investigation. We have found nuclear distribution protein C (nudC), a key component of mitosis and cytokinesis during development, to be present in the inner segment region of these postmitotic cells in several species, including mouse, tree shrew, monkey, and frog. Further, we found nudC interacts with rhodopsin and the small GTPase rab11a. Here, we show through transgenic tadpole studies that nudC is integral to rod cell disk formation and photoreceptor protein localization. Finally, we demonstrate that short hairpin RNA knockdown of nudC in tadpole rod photoreceptors, which leads to the inability of rod cells to maintain their OS, is rescued through coexpression of murine nudC.-Boitet, E. R., Reish, N. J., Hubbard, M. G., Gross, A. K. NudC regulates photoreceptor disk morphogenesis and rhodopsin localization.

Nucleotide bound to rab11a controls localization in rod cells but not interaction with rhodopsin.

Precise vectorial transport of rhodopsin is essential for rod photoreceptor health and function. Mutations that truncate or extend the C terminus of rhodopsin disrupt this transport, and lead to retinal degeneration and blindness in human patients and in mouse models. Here we show that such mutations disrupt the binding of rhodopsin to the small GTPase rab11a. The rhodopsin-rab11a interaction is a direct binding interaction that does not depend on the nucleotide binding state of rab11a. Expression of EGFP-rab11a fusion proteins in Xenopus laevis photoreceptors revealed that the nucleotide binding status of rab11a affects its subcellular localization, with GTP-locked mutants concentrated in the inner segment and GDP-locked mutants concentrated in the outer segment. shRNA-mediated knockdown of rab11a in rods led to shortened outer segments and retinal degeneration. Together, our results show the critical importance of direct rhodopsin-rab11a interactions for the formation and maintenance of vertebrate photoreceptors.

Neuropathology of Anti-Amyloid-ß Immunotherapy: A Case Report.

Host responses to anti-amyloid-ß (Aß) antibody therapy are evident in neuroimaging changes and clinical symptoms in a subset of clinical trial subjects receiving such therapy. The pathological basis for the imaging changes and clinical symptoms is not known, nor is the precise mechanism of Aß clearing. We report the autopsy findings in a 65-year-old woman who received three open label infusions of the experimental anti-Aß drug lecanemab over about one month. Four days after the last infusion, she was treated with tissue plasminogen activator for acute stroke symptoms and died several days later with multifocal hemorrhage. Neuropathological examination demonstrated histiocytic vasculitis involving blood vessels with cerebral amyloid angiopathy. Fragmentation and phagocytosis of vascular Aß were present throughout the cerebral cortex. Phagocytosis of parenchymal Aß plaques was noted. Changes suggestive of Aß and phosphorylated tau "clearing" were also noted. The findings overall suggest that anti-Aß treatment stimulated a host response to Aß, i.e., target engagement. The findings also provide evidence that amyloid-related imaging abnormalities might be indicative of an Aß phagocytic syndrome within cerebral vasculature and parenchymal brain tissue in some cases.

Abnormal movements in hospitalized COVID-19 patients: A case series.

BACKGROUND: Abnormal movements in Covid-19 patients have been reported with varying degree of frequency, prompting neurologic consultation and additional diagnostic evaluation. We sought to evaluate the frequency and etiology of abnormal movements among hospitalized Covid-19 patients undergoing neurologic consultation. METHODS: We retrospectively analyzed the first 50 consecutive patients with confirmed Covid-19 hospitalized at our tertiary medical care center who underwent acute inpatient neurology consultation from March 2020 through May 2020. Indication for neurologic consultation and diagnostic studies performed were identified by electronic medical record review. RESULTS: Of the 50 initial consultation requests, 11 (22.0%) patients were evaluated for abnormal movements (nine male and two female). Myoclonus was diagnosed in 6/11 (54.5%) patients. Additionally, two patients were diagnosed with seizures (confirmed on EEG in one), while two additional patients were diagnosed with tremor (physiologic and probable functional). A single case of serotonin syndrome was also identified. CONCLUSION: Abnormal movements observed in hospitalized Covid-19 patients can have a wide range of etiologies and were a frequent initial indication for neurologic consultation. Myoclonus was the most frequent type of abnormal movement observed. Early clinical recognition and directed diagnostic work-up is essential for accurate diagnoses in these patients.

The age-regulating protein klotho is vital to sustain retinal function.

PURPOSE: To determine whether the age-regulating protein klotho was expressed in the retina and determine whether the absence of klotho affected retinal function. METHODS: Immunohistochemistry and qPCR of klotho knockout and wild-type mice were used to detect klotho expression in retina. Immunohistochemistry was used to probe for differences in expression of proteins important in synaptic function, retinal structure, and ionic flux. Electroretinography (ERG) was conducted on animals across lifespan to determine whether decreased klotho expression affects retinal function. RESULTS: Klotho mRNA and protein were detected in the wild-type mouse retina, with protein present in all nuclear layers. Over the short lifespan of the knockout mouse (∼8 weeks), no overt photoreceptor cell loss was observed, however, function was progressively impaired. At 3 weeks of age neither protein expression levels (synaptophysin and glutamic acid decarboxylase [GAD67]) nor retinal function were distinguishable from wild-type controls. However, by 7 weeks of age expression of synaptophysin, glial fibrillary acidic protein (GFAP), and transient receptor potential cation channel subfamily member 1 (TRPM1) decreased while GAD67, post synaptic density 95 (PSD95), and wheat germ agglutinin staining, representative of glycoprotein sialic acid residues, were increased relative to wild-type mice. Accompanying these changes, profound functional deficits were observed as both ERG a-wave and b-wave amplitudes compared with wild-type controls. CONCLUSIONS: Klotho is expressed in the retina and is important for healthy retinal function. Although the mechanisms for the observed abnormalities are not known, they are consistent with the accelerating aging phenotype seen in other tissues.

Reduced expression of the NMDA receptor-interacting protein SynGAP causes behavioral abnormalities that model symptoms of Schizophrenia.

Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic-interacting proteins of these channels are abnormally expressed in some patients with this illness. In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. Here we show that reduced expression of the neuronal RasGAP and NMDAR-associated protein, SynGAP, results in abnormal behaviors strikingly similar to that reported in mice with reduced NMDAR function. SynGAP mutant mice exhibited nonhabituating and persistent hyperactivity that was ameliorated by the antipsychotic clozapine. An NMDAR antagonist, MK-801, induced hyperactivity in normal mice but SynGAP mutants were less responsive, suggesting that NMDAR hypofunction contributes to this behavioral abnormality. SynGAP mutants exhibited enhanced startle reactivity and impaired sensory-motor gating. These mice also displayed a complete lack of social memory and a propensity toward social isolation. Finally, SynGAP mutants had deficits in cued fear conditioning and working memory, indicating abnormal function of circuits that control emotion and choice. Our results demonstrate that SynGAP mutant mice have gross neurological deficits similar to other mouse models of schizophrenia. Because SynGAP interacts with NMDARs, and the signaling activity of this protein is regulated by these channels, our data in dicate that SynGAP lies downstream of NMDARs and is a required intermediate for normal neural circuit function and behavior. Taken together, these data support the idea that schizophrenia may arise from abnormal signaling pathways that are mediated by NMDA receptors.