Biology subjects

Peixoto, R. T.

Publications and source records attributed to Peixoto, R. T..

3 recordsLinked to original sources

bioRxiv2026

Structural dynamics insights into principles underlying the fitness of new broadly potent AAVs

Adeno-associated virus (AAV) is a leading platform for gene therapy, but current clinical-stage vectors require high doses associated with adverse events. Engineering of AAVs has produced more efficient vectors, although the mechanism underlying these improvements often remains poorly understood, limiting further development and raising potential safety concerns. Here, we leveraged a new workflow for AAV engineering with single-cell resolution, called scAAVengr-Hunt, to create best-in-class AAVs for gene delivery. ATX002, the top-performing vector, demonstrates broad potency across species, including nonhuman primate, mouse, and human, as well as across retina and brain. To understand the mechanism underlying this broad potency, we performed molecular dynamics simulations comparing AAV variants spanning a range of fitness levels. Structural dynamics analysis revealed a bifunctional molecular mechanism that confers potency through increased affinity of the capsid to the AAV receptor and regulation of heparan sulfate binding. This work provides critical insights relating structural mechanism to the fitness of engineered AAVs and establishes rich new avenues for AAV engineering through the integration of sequence-level analysis with computational biophysics.

bioengineering↗

bioRxiv2025

Late onset of striatal projection neuron hyperexcitability in Fmr1-/y mice

AbstractFragile X Syndrome (FXS), the most common genetic cause of intellectual disability and autism spectrum disorder (ASD), results from silencing of the FMR1 gene and consequent loss of Fragile X Messenger Ribonucleoprotein (FMRP). FMRP deficiency disrupts neural development, leading to behavioral and motor deficits associated with striatal dysfunction. While structural and functional abnormalities in striatal projection neurons (SPNs) have been observed in adult Fmr1 knockout (KO) mice, their developmental onset and contribution to early FXS pathophysiology remain unknown. In this study, we examined the postnatal maturation of SPN in the dorsomedial striatum (DMS) of Fmr1 KO mice, assessing glutamatergic synaptic inputs and intrinsic excitability. During postnatal development, Fmr1 deficient SPNs in DMS display normal synaptic and intrinsic properties, consistent with typical maturation. In contrast, by P60, SPNs of mice exhibit pronounced hyperexcitability, characterized by increased membrane resistance, reduced rheobase, and slower action potential kinetics. These perturbations affect both Dopamine 1 receptor-expressing (D1-SPN) and D2 receptor-expressing (D2-SPN) SPNs, though some action potential dynamics are selectively impaired in D1-SPNs. Chronic aripiprazole treatment, a widely prescribed therapy for FXS-related symptoms, fails to normalize SPN excitability, highlighting its limited efficacy in addressing core SPN dysfunction. Our findings reveal a late-onset hyperexcitability in DMS SPNs of Fmr1 KO mice, suggesting a progressive emergence of striatal neuron abnormalities over development. These results underscore the importance of developmental timing in FXS pathophysiology and emphasize the need for targeted interventions to address striatal circuit dysfunction.

neuroscience↗

bioRxiv2024

Early Postnatal Dysfunction of mPFC PV Interneurons in Shank3B-/- Mice

Anterior cingulate cortex (ACC) dysfunction is implicated in the cognitive and social deficits associated with autism spectrum disorder (ASD), yet the developmental trajectory of ACC circuit maturation in ASD remains poorly understood. Here, we examined the postnatal development of glutamatergic synaptic connectivity and intrinsic excitability in layer 2/3 pyramidal neurons (PYR) and Parvalbumin-expressing interneurons (PVIN) in the ACC of mice harboring a deletion in SHANK3 (Shank3B-/-), a well-established genetic cause of autism. We found that ACC PVINs in Shank3B-/- mice exhibit reduced excitability and in vivo hypoactivity as early as postnatal day 15 (P15) despite receiving normal levels of glutamatergic input. This early PVIN hypoexcitability is associated with decreased feedforward inhibition from the mediodorsal thalamus and reduced hyperpolarization-activated (Ih) currents mediated by hyperpolarization-activated cyclic nucleotide gated (HCN) channels. In contrast, PYRs display normal excitability and synaptic input at this stage but already exhibit reduced Ih currents, indicating an early emergence of HCN channel dysfunction in both PYR and PVIN. By adulthood, both neuron populations undergo marked phenotypic changes, characterized by reduced glutamatergic synaptic input and divergent alterations in excitability. Together, these findings reveal a distinct sequence of early PVIN dysfunction followed by cell-type specific circuit reorganization within ACC layer 2/3 of Shank3B-/- mice and identify HCN channelopathy and impaired PVIN-mediated inhibition as early pathogenic features of SHANK3-related neurodevelopmental disorders.

neuroscience↗