Biology subjects

von Engelhardt, J.

Publications and source records attributed to von Engelhardt, J..

6 recordsLinked to original sources

bioRxiv2026

Short-term plasticity at retinogeniculate synapses depends on synaptic strength

Relay neurons of the dorsal lateral geniculate nucleus (dLGN) receive convergent inputs from retinal ganglion cells (RGCs). Retinogeniculate synapses exhibit a highly skewed distribution of synaptic strength, with a few strong inputs and many weak ones. Strong synapses are thought to dominate relay neuron activity. However, the contribution of individual inputs might not just depend on strength but also on short-term plasticity Using minimal stimulation recordings in acute mouse brain slices, we analyzed the electrophysiological properties of individual retinogeniculate synapses. We observed a robust inverse correlation between synaptic strength and short-term plasticity: weak synapses showed facilitation, whereas strong synapses exhibited pronounced depression. This was consistent with increasing vesicle release probability and enhanced AMPA receptor desensitization at stronger synapses. Analysis of synaptic current kinetics further suggested that variability in synaptic strength reflects not only differences in synapse size and AMPA receptor content but also differences in the electrotonic distance of synapses from the soma. Together, these results reveal systematic heterogeneity in both presynaptic and postsynaptic properties of retinogeniculate synapses. Therefore, the relative contribution of weak and strong inputs to relay neuron firing is likely activity-dependent, with strong synapses dominating when RGCs fire few action potentials and weaker inputs contributing more during sustained or high-frequency firing with several action potentials.

neuroscience↗

bioRxiv2026

Serotonergic axons signal reward, sensory stimulation, and prepare for movement in primary somatosensory cortex

Serotonin is one of the main neuromodulators in the brain, involved in regulating mood, complex behaviors and sensory input. Serotonin reaches primary somatosensory cortex (S1) via axons of neurons located in the dorsal raphe nucleus (DRN). DRN neurons can be modulated, amongst others, by reward, sensory stimulation, or movement but the activity pattern of serotonergic neurons targeting S1 is not known. Therefore, it is unclear under which circumstances serotonin is released in S1. Here, we expressed GCaMP8 in serotonergic neurons of the DRN to analyze the activity of their axons in S1 using two-photon Ca2+-imaging. Cluster analysis of axonal activities suggests that one to four functional groups of serotonergic axon segments project to a 0.3 mm2 horizontal plane of S1. We show that activity in serotonergic axons is strongly driven by reward and weakly by sensory stimulation of the whiskers. Movement, however, is preceded by a modulation, up and down, of the serotonergic signal seconds before the running onset. In summary, rewards and sensory stimulation lead to activity in serotonergic axons which is likely to adjust signal processing in S1 upon these events. The serotonergic signal changes seconds before movement onset probably preparing the neural network in S1 for the state change that accompanies running.

neuroscience↗

bioRxiv2025

Reversible synaptic deficits in early-stage Batten disease

Juvenile neuronal ceroid lipofuscinosis (JNCL, Batten Disease) is a childhood-onset, neurodegenerative, lysosomal storage disorder caused by mutations in the lysosomal gene CLN3. Progressive cognitive decline is a key clinical manifestation of JNCL, and no definitive treatment is currently available. The precise function of CLN3 in neurons remains unclear, hindering the development of targeted therapies. Using patch-clamp and AAV-mediated re-expression of CLN3 in Cln3{Delta}ex7/8 mice, we demonstrate that CLN3 is essential for synaptic function. Loss of CLN3 caused defective synaptic vesicle release and reduced synaptic strength reflecting impairments in both pre- and postsynaptic function in Cln3{Delta}ex7/8 mice before the occurrence of neurodegeneration. Moreover, we observed reduced network bursting and deficits in intrinsic neuronal excitability, indicating early functional disturbances independent of storage burden and neuronal death in Cln3-deficient mice. To assess whether CLN3 is required for proper pre- and postsynaptic function, we re-expressed CLN3 selectively in pre- and postsynaptic neurons. We found non-redundant requirements at both pre- and postsynaptic sites to sustain function. Importantly, AAV9-mediated gene rescue at early-disease stages corrected preexisting synaptic defects and restored function. Together, these findings demonstrate the requirement of CLN3 in maintaining synaptic function and show that the therapeutic window may extend to stages characterized by early functional deficits, highlighting the potential of targeted gene therapy to restore function and improve cognitive outcomes.

neuroscience↗

bioRxiv2024

AMPA receptor desensitization shapes gain control in the lateral geniculate nucleus

Synaptic short-term plasticity and EPSP summation determine the processing of visual information by dLGN relay cells. In vitro studies suggested that desensitization of AMPA receptor results in pronounced short-term depression in retinogeniculate synapses thereby influencing activation of relay cells by retinal ganglion cell spikes. However, whether retinogeniculate synapses depress and whether AMPA receptors desensitize in vivo is controversial. We here tested the role of AMPA receptor desensitization in processing of visual information by generating a computational model of a dLGN relay cell containing AMPA receptors with different levels of desensitization. In addition, we investigated the in vivo activity of dLGN relay cells in wildtype and CKAMP44-/- mice. CKAMP44 is an auxiliary subunit that increases desensitization of AMPA receptors in retinogeniculate synapses. The comparison of responses of relay cells in the two genotypes therefore allowed us to obtain information about the contribution of AMPA receptor desensitization in processing of visual information. The simulations and the in vivo data show that AMPA receptor desensitization affects relay cell activity by decreasing input gain and response gain. In addition, desensitization sharpens the response of relay neurons to moving gratings in the temporal domain by decreasing the firing rate when the non-preferred stimulus is presented. Altogether, we uncover a complex role of CKAMP44 and AMPA receptor desensitization in information processing of dLGN relay neurons in vivo.

neuroscience↗

bioRxiv2023

Freezing responses during prolonged threat memory retrieval reflect trait-like anxiety endophenotypes in female and male inbred mice

Trait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the inter-individual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalized trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype biomarker in both sexes, females were consistently associated with an increased freezing response RNA-sequencing of CeA, BLA, ACC and BNST revealed massive differences in phasic and sustained responders transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly PTSD. Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner. We like to think we have constrained an organism to the task we have set. In practice, our paradigms are constrained by the way the organisms respond McNaughton & Corr, 2004

neuroscience↗

bioRxiv2018

Maternal inflammation significantly impacts cortical interneuron development in a subtype-specific manner

Severe infections during pregnancy are one of the major risk factors for cognitive brain impairment in offspring. It has been suggested that maternal inflammation leads to dysfunction of cortical GABAergic interneurons that in turn underlies cognitive impairment of the affected offspring. However, the evidence comes largely from studies of adult or mature brain and how impairment of inhibitory circuits arises upon maternal inflammation is unknown. Here we show that maternal inflammation affects multiple steps of cortical GABAergic interneuron development, i.e. proliferation of precursor cells, migration and positioning of neuroblasts as well as neuronal maturation. Importantly, the development of distinct subtypes of cortical GABAergic interneurons was discretely impaired as a result of maternal inflammation. This translated into a reduction in cell numbers, redistribution across cortical regions and layers, changes in morphology and cellular properties. Furthermore, selective vulnerability of GABAergic interneuron subtypes was associated with the stage of brain development. Thus, we propose that maternally-derived insults have developmental stage-dependent effects which contribute to the complex etiology of cognitive impairment in the affected offspring.

neuroscience↗