Biology subjects

Longley, C. M.

Publications and source records attributed to Longley, C. M..

4 recordsLinked to original sources

bioRxiv2026

Synaptic input-selective homeostasis safeguards developing cortical neurons toward setpoint activity

Homeostatic plasticity stabilizes brain function by maintaining neuronal activity around a setpoint. Although homeostatic mechanisms are well characterized in mature circuits, it remains unknown how developing neurons, which progress from near silence at birth to sustained activity, establish and safeguard their setpoint activity levels against perturbations. Here we show that activity setpoints are intrinsic properties of neuronal identity actively achieved by cell-autonomous, targeted synaptic remodeling during development. Cortical layer 2/3 pyramidal cells were sparsely silenced from their birth by overexpressing the inward-rectifier potassium channel Kir2.1 to chronically suppress their excitability. These Kir2.1-expressing neurons, however, progressively overcame this perturbation during postnatal development and ultimately reached the activity levels comparable to neighboring control neurons. This recovery was accompanied by enhanced synaptic excitation and reduced inhibition that did not follow the classical global multiplicative synaptic scaling. Instead, excitation from infragranular layers, rather than layer 4 and layer 2/3, was selectively strengthened through increasing quantal amplitudes and unsilencing silent synapses that required the insertion of GluA2-containing AMPA receptors. Inhibition recruited by excitatory inputs was selectively reduced at specific pathways. These results identify a synaptic input-selective homeostatic program enabling cortical neurons to reach activity setpoints, revealing a new mechanism contributing to neurodevelopmental robustness.

neuroscience↗

bioRxiv2022

Cell-type specific deletions of Neuroligin 2 reveal a vital role of synaptic excitation-inhibition balance

Synaptic excitation (E) and inhibition (I) stay relatively proportional to each other over different spatiotemporal scales, orchestrating neuronal activity in the brain. This proportionality, referred to as E-I balance, is thought to be critical for neuronal functions because its disruption was observed in many neurological disorders. However, the causal evidence demonstrating its significance is scarce. Here we show that deleting Neuroligin-2 (Nlgn2), a postsynaptic adhesion molecule at inhibitory synapses, from mouse glutamatergic or GABAergic neurons reduces inhibition cell-autonomously without affecting excitation, thereby disrupting E-I balance and causing lethality. In contrast, deleting Nlgn2 constitutively or simultaneously from both glutamatergic and GABAergic neurons results in viable mice. A neural network model shows that reducing inhibition in either neuronal type is detrimental to network activity, but in both types partially re-establishes E-I balance and activity. Together, our results provide evidence for an essential role of E-I balance in brain functions and organism survival.

neuroscience↗

bioRxiv2021

Ankyrin-R regulates fast-spiking interneuron excitability through perineuronal nets and Kv3.1b K+ channels

Neuronal ankyrins cluster and link membrane proteins to the actin and spectrin-based cytoskeleton. Among the three vertebrate ankyrins, little is known about neuronal Ankyrin-R (AnkR). We report AnkR is highly enriched in Pv+ fast-spiking interneurons in mouse and human. We identify AnkR-associated protein complexes including cytoskeletal proteins, cell adhesion molecules (CAMs), and perineuronal nets (PNNs). We show that loss of AnkR from forebrain interneurons reduces and disrupts PNNs, decreases anxiety-like behaviors, and changes the intrinsic excitability and firing properties of Pv+ fast-spiking interneurons. These changes are accompanied by a dramatic reduction in Kv3.1b K+ channels. We identify a novel AnkR-binding motif in Kv3.1b, and show that AnkR is both necessary and sufficient for Kv3.1b membrane localization in interneurons and at nodes of Ranvier. Thus, AnkR regulates Pv+ fast-spiking interneuron function by organizing ion channels, CAMs, and PNNs, and linking these to the underlying {beta}1 spectrin-based cytoskeleton.

neuroscience↗

bioRxiv2021

Drosophila functional screening of de novo variants in autism uncovers deleterious variants and facilitates discovery of rare neurodevelopmental diseases

Individuals with autism spectrum disorders (ASD) exhibit an increased burden of de novo variants in a broadening range of genes. We functionally tested the effects of ASD missense variants using Drosophila through humanization rescue and overexpression-based strategies. We studied 79 ASD variants in 74 genes identified in the Simons Simplex Collection and found 38% of them caused functional alterations. Moreover, we identified GLRA2 as the cause of a spectrum of neurodevelopmental phenotypes beyond ASD in eight previously undiagnosed subjects. Functional characterization of variants in ASD candidate genes point to conserved neurobiological mechanisms and facilitates gene discovery for rare neurodevelopmental diseases.

genetics↗