Biology subjects

Zytnicki, D.

Publications and source records attributed to Zytnicki, D..

3 recordsLinked to original sources

bioRxiv2026

Defective synapto-nuclear signaling contributes to motoneuron vulnerability in SOD1-ALS

Glutamatergic excitatory synapses not only shape spiking activity and neuronal communication but also initiate activity-dependent signaling pathways that trigger transcriptional programs. Since glutamatergic excitatory synapses onto spinal motoneurons (MNs) are impaired presymptomatically in Amyotrophic Lateral Sclerosis, we investigated whether synapto-nuclear coupling is disrupted in MNs from mSOD1 mice and whether restoring it mitigates pathology. We developed an in vivo approach to selectively investigate the coupling between synaptic excitation and nuclear CREB phosphorylation in spinal MNs. Specific activation of Ia-MN synapses induces CREB phosphorylation in wild-type MNs but not in mSOD1 MNs at P50, indicating presymptomatic synapto-nuclear uncoupling. Enhancing cAMP/PKA signaling by pharmacological inhibition of cAMP degradation restored synapto-nuclear coupling, reduced misfolded SOD1, and slowed neuromuscular-junction denervation. Thus, activity-dependent synapto-nuclear signaling is impaired yet pharmacologically rescuable in mSOD1 MNs, supporting synapto-nuclear signaling as a determinant of MN resilience.

neuroscience↗

bioRxiv2024

Spinal microcircuits go through multiphasic homeostatic compensations in a mouse model of motoneuron degeneration

In many neurological conditions, early-stage neural circuit adaption can preserve relatively normal behaviour. In some diseases, spinal motoneurons progressively degenerate yet movement is initially preserved. We therefore investigated whether these neurons and associated microcircuits adapt in a mouse model of progressive motoneuron degeneration. Using a combination of in vitro and in vivo electrophysiology and super-resolution microscopy, we found that, early in the disease, neurotransmission in a key pre-motor circuit, the recurrent inhibition mediated by Renshaw cells, is reduced by half due to impaired quantal size associated with decreased glycine receptor density. This impairment is specific, and not a widespread feature of spinal inhibitory circuits. Furthermore, it recovers at later stages of disease. Additionally, an increased probability of release from proprioceptive afferents leads to increased monosynaptic excitation of motoneurons. We reveal that in motoneuron degenerative conditions, spinal microcircuits undergo specific multiphasic homeostatic compensations that may contribute to preservation of force output.

neuroscience↗

bioRxiv2024

Non-canonical adrenergic neuromodulation of motoneuron intrinsic excitability through beta-receptors in wild-type and ALS mice

Homeostatic feedback loops are essential to stabilize the activity of neurons and neuronal networks. It has been hypothesized that, in the context of Amyotrophic Lateral Sclerosis (ALS), an excessive gain in feedback loops might hyper- or hypo-excite motoneurons (MNs) and contribute to the pathogenesis. Here, we investigated how the neuromodulation of MN intrinsic properties is homeostatically controlled in presymptomatic adult SOD1(G93A) mice and in the age-matched control WT mice. First, we determined that {beta}2 and {beta}3-adrenergic receptors, which are Gs-coupled receptors and subject to tight and robust feedback loops, are specifically expressed in spinal MNs of both SOD1 and WT mice at P45. We then demonstrated that these receptors elicit a so-far overlooked neuromodulation of the firing and excitability properties of MNs. These electrical properties are homeostatically regulated following receptor engagement, which triggers ion channel transcriptional changes and downregulates those receptors. These homeostatic feedbacks are not dysregulated in presymptomatic SOD1 mice, and they set the MN excitability upon {beta}-adrenergic neuromodulation.

neuroscience↗