Biology subjects

Basilico, B.

Publications and source records attributed to Basilico, B..

5 recordsLinked to original sources

bioRxiv2025

Missense mutations on SynGAP C2 domain impair membrane diffusion

SYNGAP1 mutations have been linked to a range of neuropathological disorders and, more recently, to the insurgence of cancer. Despite its emerging relevance, the molecular basis of SynGAPs action remains poorly understood. Here, using extensive molecular dynamics simulations integrated with structural analysis, we define how the SynGAP C2 domain associates with lipid bilayers. In particular, we observed spontaneous membrane binding of the domain in two distinct orientations, top and side, defined by the relative positioning of the C2 domain to its fold. These modes display markedly different dynamical properties: the top mode enables faster lateral diffusion on the membrane surface, whereas the side mode establishes more stable but less mobile contacts. Interestingly, pathogenic missense mutations mapping to the membrane-facing loops of SynGAP C2 disrupt these dynamics, leading to reduced diffusivity and altered membrane avidity. Our findings reveal a dual binding mechanism that underlies SynGAPs membrane versatility and offer a general framework for how diverse mutations may perturb SynGAP activity across its polyedric biological functions.

biophysics↗

bioRxiv2022

Large neutral amino acid levels tune perinatal neuronal excitability and survival

Surprisingly little is known about the critical metabolic changes that neural cells have to undergo during development and how even mild, temporary shifts in this program can influence brain circuitries and behavior. Inspired by the discovery that mutations in SLC7A5, a transporter of metabolically-relevant large neutral amino acids, lead to a form of autism spectrum disorder, we employed metabolomic profiling to study the metabolic states of the cerebral cortex across different stages of life. We found that the cerebral cortex undergoes significant metabolic remodeling throughout development, with certain groups of metabolites showing stage-specific changes. But what are the consequences of interfering with this metabolic program? By manipulating Slc7a5 expression in neural cells, we found that the metabolism of large neutral amino acids and lipids in the cerebral cortex are highly interconnected. Deletion of Slc7a5 in neurons perturbs specifically the postnatal metabolic state leading to a shift in lipid metabolism and a stage- and cell-type-specific alteration in neuronal activity patterns, resulting in a long-term cortical circuit dysfunction.

neuroscience↗

bioRxiv2021

Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

Complement signaling is thought to serve as an opsonization signal to promote the phagocytosis of synapses by microglia. However, while its role in synaptic remodeling has been demonstrated in the retino-thalamic system, it remains unclear whether complement signaling mediates synaptic pruning in the brain more generally. Here we show that mice lacking the complement 3 receptor (C3r), the major microglia complement receptor, fail to show a deficit in either synaptic pruning or axon elimination in the developing mouse cortex. Instead, mice lacking C3r show a deficit in the perinatal elimination of neurons, both in the retina as well as in the cortex, a deficit that is associated with increased cortical thickness and enhanced functional connectivity in these regions in adulthood. These data demonstrate a preferential role for complement in promoting neuronal elimination in the developing brain and argue for a reconsideration of the role of complement in synaptic pruning.

neuroscience↗

bioRxiv2021

Microglia control glutamatergic synapses in the adult mouse hippocampus

Microglial cells are active players in regulating synaptic development and plasticity in the brain. However, how these cells influence the normal functioning of synapses is largely unknown. In this study, we characterized the effects of pharmacological depletion of microglia, achieved by administration of PLX5622, on hippocampal CA3-CA1 synapses of adult wild type mice. Following microglial depletion, we observed a reduction of spontaneous and evoked glutamatergic activity associated with a decrease of dendritic spine density. We also observed the appearance of immature synaptic features accompanied by higher levels of plasticity. In addition, microglia depleted mice showed a deficit in the acquisition of the Novel Object Recognition task. Remarkably, microglial repopulation after PLX5622 withdrawal was associated with the recovery of hippocampal synapses and learning functions. Altogether, these data demonstrate that microglia contribute to normal synaptic functioning in the adult brain and that their removal induces reversible changes in synaptic organization and activity of glutamatergic synapses.

neuroscience↗

bioRxiv2020

Cul3 regulates cytoskeleton protein homeostasis and cell migration during a critical window of brain development

De novo loss of function mutations in the ubiquitin ligase-encoding gene Cullin3 (CUL3) lead to autism spectrum disorder (ASD). Here, we used Cul3 mouse models to evaluate the consequences of Cul3 mutations in vivo. Our results show that Cul3 haploinsufficient mice exhibit deficits in motor coordination as well as ASD-relevant social and cognitive impairments. Cul3 mutant brain displays cortical lamination abnormalities due to defective neuronal migration and reduced numbers of excitatory and inhibitory neurons. In line with the observed abnormal columnar organization, Cul3 haploinsufficiency is associated with decreased spontaneous excitatory and inhibitory activity in the cortex. At the molecular level, employing a quantitative proteomic approach, we show that Cul3 regulates cytoskeletal and adhesion protein abundance in mouse embryos. Abnormal regulation of cytoskeletal proteins in Cul3 mutant neuronal cells results in atypical organization of the actin mesh at the cell leading edge, likely causing the observed migration deficits. In contrast to these important functions early in development, Cul3 deficiency appears less relevant at adult stages. In fact, induction of Cul3 haploinsufficiency in adult mice does not result in the behavioral defects observed in constitutive Cul3 haploinsufficient animals. Taken together, our data indicate that Cul3 has a critical role in the regulation of cytoskeletal proteins and neuronal migration and that ASD-associated defects and behavioral abnormalities are primarily due to Cul3 functions at early developmental stages.

neuroscience↗