Biology subjects

Galloni, A. R.

Publications and source records attributed to Galloni, A. R..

4 recordsLinked to original sources

bioRxiv2026

GIRK Channel Loss of Function Increases Dendritic Excitability in a Mouse Model of GNB1 Encephalopathy

GNB1 encephalopathy (GNB1-E) is a rare neurodevelopmental disorder associated with motor dysfunction, epilepsy and learning disability caused by mutations in the gene encoding the G protein subunit G{beta}1. Previous work has shown that altered G{beta}1 can disrupt activation of G-protein-coupled inwardly rectifying potassium (GIRK) channels, dysregulate neuronal excitability and cause seizures. However, the relevant upstream regulators of G{beta}1 and the consequences of GIRK dysfunction for neuronal synaptic, cellular and circuit function have not been characterized. Here we report that mice of both sexes carrying the deleterious p.I80T mutation in Gnb1 present features consistent with GNB1-E, including developmental delay, decreased locomotion and increased anxiety. Using histology, whole-cell patch-clamp electrophysiology and pharmacology in ex vivo brain slices, we find that hippocampal neurons in heterozygous Gnb1I80T/+ mice exhibit simplified dendritic morphologies, decreased synaptic inhibition mediated by metabotropic GABAB receptors and increased dendritic excitability. These phenotypes result in longer duration dendritic calcium spikes in response to synaptic afferent stimulation, an effect that is reversed by a specific activator of GIRK channels, ML297. Given the known roles of dendritic calcium spikes in driving burst firing and inducing synaptic plasticity, these findings suggest that targeting dendritic excitability has therapeutic potential to address both the seizure susceptibility and learning deficits associated with GNB1-E. Significance StatementGNB1 encephalopathy (GNB1-E) is a rare neurodevelopmental disorder associated with motor dysfunction, epilepsy and learning disability for which there are currently no mechanism-based treatments. Here we show that a pathogenic variant of the G protein subunit G{beta}1 impairs activation of neuronal G-protein-coupled inwardly rectifying potassium (GIRK) channels by inhibitory synaptic GABAB receptors. This leads to increased dendritic excitability and longer duration dendritic calcium spikes in mouse hippocampal neurons in response to stimulation of synaptic inputs. We find that this phenotype is reversed by a drug that activates GIRK channels, opening pathways to develop therapies for GNB1-E that specifically target dendritic excitability.

neuroscience↗

bioRxiv2025

Cellular and subcellular specialization enables biology-constrained deep learning

Learning and memory in the brain depend on changes in the strengths of synaptic connections between neurons. While the molecular and cellular mechanisms of synaptic plasticity have been extensively studied experimentally, much of our understanding of how plasticity is organized across populations of neurons during task learning comes from training artificial neural networks (ANNs) using computational methods. However, the architectures of modern ANNs and the algorithms used to train them are not compatible with fundamental principles of neuroscience, leaving a gap in understanding how the brain coordinates learning across multiple layers of neural circuitry. Here we leverage recent experimental evidence to test an emergent theory that biological learning depends on specialization of distinct neuronal cell types and compartmentalized signaling within neuronal dendrites. We demonstrate that multilayer ANNs comprised of separate recurrently connected excitatory and inhibitory cell types, and neuronal units with separate soma and dendrite compartments, can be trained to accurately classify images using a fully biology-compatible deep learning algorithm called dendritic target propagation. By adhering to strict biological constraints, this model is able to provide unique insight into the biological mechanisms of learning and to make experimentally testable predictions regarding the roles of specific neuronal cell types in coordinating learning across different brain regions.

neuroscience↗

bioRxiv2021

Dendritic domain-specific sampling of long-range axons shapes feedforward and feedback connectivity of L5 neurons

Feedforward and feedback pathways interact in specific dendritic domains to enable cognitive functions such as predictive processing and learning. Based on axonal projections, hierarchically lower areas are thought to form synapses primarily on dendrites in middle cortical layers, while higher-order areas are posited to target dendrites in layer 1 and in deep layers. However, the extent to which functional synapses form in regions of axo-dendritic overlap has not been extensively studied. Here, we use viral tracing in the secondary visual cortex of mice to map brain-wide inputs to thick-tufted layer 5 pyramidal neurons. Furthermore, we provide a comprehensive map of input locations through subcellular optogenetic circuit mapping. We show that input pathways target distinct dendritic domains with far greater specificity than appears from their axonal branching, often deviating substantially from the canonical patterns. Common assumptions regarding the dendrite-level interaction of feedforward and feedback inputs may thus need revisiting.

neuroscience↗

bioRxiv2019

Apical length modulates dendritic excitability in L5 pyramidal neurons

Anatomical similarity across the neocortex has led to the common assumption that the circuitry is modular and performs stereotyped computations. Layer 5 pyramidal neurons (L5PNs) in particular are thought to be central to cortical computation because of their extensive arborisation and nonlinear dendritic operations. Here, we demonstrate that computations associated with dendritic Ca2+ plateaus in L5PNs vary substantially between the primary and secondary visual cortices. L5PNs in the secondary visual cortex show reduced dendritic excitability and smaller propensity for burst firing. This reduced excitability is correlated with shorter apical dendrites. Using numerical modelling, we uncover a universal principle underlying the influence of apical length on dendritic backpropagation and excitability, based on a Na+ channel-dependent broadening of backpropagating action potentials. In summary, we provide new insights into the modulation of dendritic excitability by apical dendrite length and show that the operational repertoire of L5 neurons is not universal throughout the brain.

neuroscience↗