Biology subjects

Yarom, Y.

Publications and source records attributed to Yarom, Y..

5 recordsLinked to original sources

bioRxiv2026

IL-17A rescues motor deficits in a mouse model 1 of Spinocerebellar Ataxia Type 2

Motor performance and coordination deficits are hallmarks of spinocerebellar ataxias, yet effective disease-modifying therapies remain limited. Here, we investigate the expression of the interleukin 17 receptor subunit A (IL-17RA) in cerebellum and assess the therapeutic potential of its ligand in a mouse model for Spinocerebellar Ataxia Type 2 (SCA2). We found that IL-17RA is highly enriched in cerebellar molecular layer interneurons (MLIs), which provide inhibitory input to Purkinje neurons. In-vitro electrophysiological recordings revealed that symptomatic SCA2 mice exhibited increased spontaneous inhibitory synaptic input onto Purkinje neurons, which was normalized by IL-17A application to control levels. Concomitantly, IL-17A application restored Purkinje neuron firing, a parameter characteristically reduced in SCA2 mice. Behaviorally, intranasal administration of IL-17A restored motor performance of symptomatic SCA2 mice to control levels in both rotarod and beam-crossing assays. Collectively, our results indicate that IL-17A rescues Purkinje neuron dysfunction and motor deficits in SCA2 mice, highlighting IL-17A signaling as a promising therapeutic target for spinocerebellar ataxia.

neuroscience↗

bioRxiv2024

Adaptation of pain-related projection neurons in acute but not chronic pain

Pain hypersensitivity is associated with increased activity of peripheral and central neurons along the pain neuroaxis1. On the other hand, in other neuronal systems, increased activity leads to adaptive reduction of neuronal excitability to maintain homeostasis2-4. Projection neurons (PNs) of spinal and medullary dorsal horns summate the activity of primary nociceptive and local central interneurons and convey it to higher centers5. We show that at the peak of acute inflammatory pain, PNs reduce their intrinsic excitability and, consequently, action potential firing. When pain resolves, the excitability of PNs returns to baseline. Using electrophysiological and computational approaches, we found that an increase in potassium A-current (IA) underlies the decrease in the excitability of PNs in acute pain conditions. We hypothesized that an IA-induced decrease in PNs firing may restrain the output from the dorsal horn to prevent sensitization and pain chronification. Indeed, no changes of IA in PNs were observed in chronic pain conditions, and PNs exhibit increased intrinsic excitability and firing. Our results reveal an adaptive mechanism in acute pain conditions for regulating the output from the dorsal horn network, which, if interrupted, could trigger pain chronification.

neuroscience↗

bioRxiv2023

Human outperform mouse Purkinje cells in dendritic complexity and computational capacity

Purkinje cells (PC) of the cerebellum are amongst the largest neurons of the brain and have been extensively investigated in rodents. However, their morphological and physiological properties in humans are still poorly understood. Here, we have taken advantage of high-resolution morphological reconstructions and of unique electrophysiological recordings of human PCs ex vivo to generate computational models and estimate computational capacity. An inter-species comparison showed that human PCs had similar fractal structure but were bigger than mouse PCs. Consequently, given a similar spine density (2/m), human PCs hosted about 5 times more dendritic spines. Moreover, human had higher dendritic complexity than mouse PCs and usually emitted 2-3 main dendritic trunks instead than 1. Intrinsic electroresponsiveness was similar in the two species but model simulations revealed that the dendrites generated ~6.5 times (n=51 vs. n=8) more combinations of independent input patterns in human than mouse PCs leading to an exponential 2n increase in Shannon information. Thus, while during evolution human PCs maintained similar patterns of spike discharge as in rodents, they developed more complex dendrites enhancing computational capacity up to the limit of 10 billion times.

neuroscience↗

bioRxiv2018

Using subthreshold events to characterize the functional architecture of electrically coupled networks

The electrical connectivity in the inferior olive (IO) nucleus plays an important role in generating well-timed spiking activity. Here we combined electrophysiological and computational approaches to assess the functional organization of mice IO nucleus. Spontaneous fast and slow subthreshold events were commonly encountered during in vitro recordings. We show that the fast events represent a regenerative response in unique excitable spine-like structures in the axon hillock, whereas the slow events reflect the electrical connectivity between neurons ( spikelets). Recordings from cell pairs revealed the synchronized occurrence of distinct groups of spikelets; their rate and distribution enabled an accurate estimation of the number of connected cells and is suggestive of a clustered organization. This study thus provides a new perspective on the functional and structural organization of the olivary nucleus, insights into two different subthreshold non-synaptic events, and a novel experimental and theoretical approach to the study of electrically-coupled networks.

neuroscience↗

bioRxiv2018

Pogz deficiency leads to abnormal behavior, transcription dysregulation and impaired cerebellar physiology

Genes implicated in autism spectrum disorder (ASD) are enriched with chromatin regulators, but the mechanisms leading to the abnormal behavior and cognition are still unclear. Animal models are crucial for studying the effects of mutations on brain function and behavior. We generated conditional knockout mice with brain-specific mutation in Pogz, a heterochromatin regulator recurrently mutated in ASD and other neurodevelopmental disorders, and demonstrated that these mice display phenotypes that resemble the human condition. Pogz deficiency led to smaller brain, growth impairment, motor learning deficits, and increased social interactions that mimic the human overly friendly phenotype. At the molecular level, reporter assay indicated that POGZ functions as a negative regulator of transcription through its interaction with HP1 proteins. In accordance, we found a significant upregulation of gene expression, most notably in the cerebellum. Furthermore, Pogz deficiency was associated with a significant reduction in the firing frequency of simple and complex spikes in cerebellar Purkinje cells with no changes in their intrinsic properties. Overall, our findings support a mechanism linking heterochromatin dysregulation to cerebellar circuit dysfunction and to motor and social abnormalities in ASD.

neuroscience↗