Biology subjects

Leffler, J.

Publications and source records attributed to Leffler, J..

5 recordsLinked to original sources

bioRxiv2026

A pooled genetic approach provides multimodal access to uncharacterized retinal ganglion cell subtypes

Retinal ganglion cells (RGCs) are the sole output neurons of the retina, responsible for transmitting visual information to the brain. Recent transcriptomic studies have revealed extensive molecular diversity among RGCs that parallels their known morphological and functional heterogeneity. Although large-scale efforts have unified the transcriptomic, morphological, and physiological features for a limited number of RGC subtypes, the majority of molecularly defined types remain poorly characterized. Developing approaches that can be used to identify RGC subtypes in a reliable and reproducible manner is critical for understanding their roles in visual processing. We used a MafbmCherry-2A-Cre mouse line to genetically label four uncharacterized RGC subtypes, along with two well-established -RGC subtypes, and we systematically characterized their molecular markers, central brain targets, dendritic morphologies, and light response properties. Within the population of previously uncharacterized MAFB+ RGCs, we identified two OFF-responsive subtypes which we termed "MAFB-midi-OFF" and "MAFB-asymmetric-OFF", and two ON-OFF-responsive subtypes termed "MAFB-equal bistratified" and "MAFB-unequal bistratified". Notably, no single molecular, morphological, or functional characteristic was sufficient to distinguish all MAFB+ subtypes. Instead, accurate subtype classification emerged only through the integration of multiple complementary features, highlighting the importance of multimodal approaches for defining RGC subtype identity and resolving neuronal diversity within the retina.

neuroscience↗

bioRxiv2025

PTEN regulates starburst amacrine cell dendrite morphology during development

Neurons are subject to extensive developmental regulation to ensure precise subtype-specific morphologies that are intimately tied to their function. Starburst amacrine cells (SACs) in the mammalian retina have a highly stereotyped, radially symmetric dendritic arbor that is essential for their role in direction-selective circuits in the retina. We show that PTEN, the primary negative regulator of the PI3K-AKT-mTOR pathway that is highly implicated in neurodevelopmental disorders, regulates SAC morphology in a cell-autonomous manner. Pten-deficient SACs show a nearly twofold increase in the number of dendritic branches, while other morphological properties remain largely unchanged. These morphological changes arise late in SAC development after dendrite development is largely complete and persist into adulthood. Mechanistically, excessive dendritic branching appears to arise from dysregulated mTOR activity. Despite this dramatic increase in dendritic branches, Pten-deficient SACs maintain a normal population number, organization of synaptic outputs, and intact direction-selectivity in the retina. Collectively, these results show that PTEN is essential for the normal development of highly stereotyped neuronal morphology.

neuroscience↗

bioRxiv2023

Functional subtypes of rodent melanopsin ganglion cells switch roles between night and day illumination.

Intrinsically photosensitive retinal ganglion cells (ipRGCs), contain the photopigment melanopsin, and influence both image and non-image forming behaviors. Despite being categorized into multiple types (M1-M6), physiological variability within these types suggests our current understanding of ipRGCs is incomplete. We used multi-electrode array (MEA) recordings and unbiased cluster analysis under synaptic blockade to identify 8 functional clusters of ipRGCs, each with distinct photosensitivity and response timing. We used Cre mice to drive the expression of channelrhodopsin in SON-ipRGCs, enabling the localization of distinct ipRGCs in the dorsal retina. Additionally, we conducted a retrospective unbiased cluster analysis of ipRGC photoresponses to light stimuli across scotopic, mesopic, and photopic intensities, aimed at activating both rod and cone inputs to ipRGCs. Our results revealed shared and distinct synaptic inputs to the identified functional clusters, demonstrating that ipRGCs encode visual information with high fidelity at low light intensities, but poorly at photopic light intensities, when melanopsin activation is highest. Collectively, our findings support a framework with at least 8 functional subtypes of ipRGCs, each encoding luminance with distinct spike outputs, highlighting the inherent functional diversity and complexity of ipRGCs and suggesting a reevaluation of their contributions to retinal function and visual perception under varying light conditions.

neuroscience↗

bioRxiv2020

Gbx2 identifies two amacrine cell subtypes with distinct molecular, morphological, and physiological properties

Our understanding of how the nervous sytem works is limited by our ability to identify the neuronal subtypes that comprise functional circuits. Using a genetic approach, we show that the transcription factor Gbx2 labels two amacrine cell (AC) subtypes in the mouse retina that have distinct morphological, physiological, and molecular properties. One subtype of Gbx2+ ACs are likely the previously characterized On-type GABAergic CRH-1 AC. The other Gbx2+ AC population is a previously uncharacterized non-GABAergic, non-Glycinergic (nGnG) AC subtype. Gbx2+ nGnG ACs are On-Off type cells with asymmetric dendritic arbors. Gbx2+ nGnG ACs also exhibit tracer coupling to bipolar cells (BCs) through gap junctions that are modulated by dopamine signaling. This study genetically identifies a previously uncharacterized AC subtype and reveals an unusual AC-BC connectivity through gap junctions that may provide a novel model of synaptic communication and visual circuit function.

neuroscience↗

bioRxiv2017

Transplacental protection against asthma by maternal treatment with a bacterial-derived immunomodulatory agent

Studies in European and US farming populations have documented major reductions in asthma prevalence in offspring of mothers exposed to microbial breakdown products present in farm dusts and unprocessed foods. This was associated with enhancement of innate immune competence in the offspring. We sought to (i) identify a safe therapeutic that would reproduce these immunomodulatory effects in a murine model, (ii) elucidate underlying mechanism(s)-of-action, and (iii) develop a scientific rationale for progressing this approach to human trials. We demonstrate in mice that maternal treatment during pregnancy with the microbial-derived immunomodulator OM85, which has been used clinically in adults and children in Europe for >30 years for bolstering resistance to infection-associated airways inflammation, markedly reduces the susceptibility of the offspring of treated mothers to development of experimental atopic asthma. We identify bone marrow precursors of the dendritic cell populations responsible for airway mucosal immune surveillance as the primary targets for the asthma-protective effects of maternal OM85 treatment in the offspring.

immunology↗