Burger, R. M. | bioRxiv Science

bioRxiv2026

Autophagy induction mitigates FUS aggregate formation and early synaptic dysfunction at the NMJ in the FUS-ALS model

Mutations in Fused in Sarcoma (FUS), a RNA binding protein, cause Amyotrophic Lateral Sclerosis (ALS). ALS is an aggressive neurodegenerative disease resulting in motor neuron degeneration. Defects in synaptic integrity precede neuronal loss in ALS, but the mechanisms responsible for these early synaptic defects are unclear. To investigate early synaptic defects associated with ALS, we expressed an ALS-linked variant of human FUS in adult motor neurons and assessed synaptic pathology at the neuromuscular junction (NMJ). Here we highlight the accumulation of FUS-positive aggregates at synaptic terminals and subsequent reduction in microtubule stability. We show that inducing autophagy via expression of Rab1 or Fragile-X Mental Retardation Protein 1 (FMR1), or treatment with Rapamycin reduces aggregate formation and restores synaptic structure and function. These findings reveal the utility of inducing autophagy to address early synaptic dysfunction in an ALS model and demonstrate a potential therapeutic target to preventing later stages of disease progression.

neuroscience↗

bioRxiv2025

Hyperpolarization-activated cation channels confer tonotopic specialization for temporal encoding of sound frequency in the cochlear nucleus

Sensory neurons are equipped with physiological properties vital for accurate signal processing. The functional importance of such properties is exemplified in auditory circuits where intrinsic excitability is optimized to detect frequency-specific features. In birds, the neurons of nucleus magnocellularis (NM) receive primary auditory input (Rubel and Parks, 1975a; Parks and Rubel, 1978; Jackson et al., 1982) and are arranged tonotopically. NM comprises a superficially homogenous neural population, but several physiological properties vary systematically along its tonotopic frequency axis. In particular, expression of voltage-gated conductances plays a pivotal role in creating selectivity that enables temporal precision. Here, we identify a previously undescribed gradient of hyperpolarization-activated cation channels (IH). Whole cell patch clamp techniques and immunostaining for HCN1, an IH channel subunit, demonstrated an expression gradient corresponding to NMs tonotopic axis. To investigate the function of tonotopic IH expression in NM, we applied a depolarizing ramp injection protocol to measure the impact of pharmacologically blocking IH on neural active properties (Ferragamo and Oertel, 2002; McGinley and Oertel, 2006; Oline et al. 2016). Next, we investigated whether this tonotopic patterning of HCN facilitates encoding of temporally patterned inputs. We injected depolarizing current pulse trains before and during HCN channel block. During pharmacological block, there was a reduction of NM spike entrainment to input pulses suggesting a key contribution of HCN channels to NMs ability to encode its synaptic drive. Results show that there is tonotopic distribution of HCN channels in NM which provides a novel mechanism that enables NM neurons to encode temporally patterned excitatory input. Significance StatementThis study is the first to describe a tonotopic gradient of IH channels in a vertebrate cochlear nucleus. Physiological and computational model assays suggest that the tonotopic expression pattern of HCN channels enables improved neural encoding of high frequency, temporally patterned input. Temporal response fidelity enables precise sound localization computations.

neuroscience↗