Biology subjects

Schmidt-Hieber, C.

Publications and source records attributed to Schmidt-Hieber, C..

5 recordsLinked to original sources

bioRxiv2026

Anti-GABAB receptor autoimmunity causes cognitive decline by presynaptic pathology

The GABAB receptor is a central regulator of neuronal transmission and excitability by pre- and postsynaptic mechanisms. Its dysfunction causes severe neurological disease, but the underlying pathomechanisms remain elusive. Here, we exploit a distinct CNS autoimmune disorder in which patients develop specific autoantibodies against GABAB receptors causing autoimmune encephalitis with severe memory dysfunction and epilepsy. We demonstrate that human autoantibodies target the sushi-domains of the GABAB receptor B1a subunit and the B2 subunit and interfere with presynaptic signaling. This specific presynaptic pathology results from exclusive functional antagonism of the B1a subunit and disrupts short- and long-term synaptic plasticity, abnormally amplifies hippocampal network oscillations and coupling in vivo, and ultimately impairs memory consolidation. Our results demonstrate that autoimmune presynaptic pathomechanisms alone are sufficient to interfere with memory processing, thus defining a causal link between molecular GABAB receptor disturbance, synaptic pathology, circuit dysfunction, and dementia distinct from classical neurodegenerative processes.

neuroscience↗

bioRxiv2025

Task engagement differentially drives hippocampal and neocortical neural codes

Sensory inputs are progressively transformed into internal representations of the environment along the cortical hierarchy. How does the behavioral relevance of these inputs affect this encoding? Using two-photon calcium imaging in mice navigating virtual-reality environments, we found that visual cortex maintained high sensory discrimination regardless of behavioural engagement, whereas the hippocampal dentate gyrus required active navigation for effective discrimination. These findings suggest that sensory cortices act as general-purpose sensory discriminators, while the hippocampus filters information based on task relevance.

neuroscience↗

bioRxiv2021

Inhibitory control of synaptic signals preceding motor action in mouse frontal cortex

Preparatory activity in the frontal cortex preceding movement onset is thought to represent a neuronal signature of motor planning. However, how excitatory and inhibitory synaptic inputs to frontal neurons are integrated during movement preparation remains unclear. Here we address this question by performing in vivo whole-cell patch-clamp recordings in the secondary motor cortex (MOs) of head-fixed mice moving on a treadmill. We find that both superficial and deep principal neurons show slowly increasing (~10 s) membrane potential and spike rate ramps preceding the onset of spontaneous, self-paced running periods. By contrast, in animals trained to perform a goal-directed task, both membrane potential and spike ramps are characterized by larger amplitudes and accelerated kinetics during preparation of goal-driven movement. To determine the role of local inhibitory neurons in shaping these task-dependent preparatory signals, we chemogenetically suppressed the activity of specific interneuron subpopulations in untrained animals. Inactivation of parvalbumin-positive (PV+) interneurons leads to depolarized membrane potential ramps with increased amplitudes during preparation of movement, while inactivation of somatostatin-positive (SOM+) interneurons abolishes membrane potential ramps. A computational model of the local MOs circuit shows that SOM+-mediated inhibition of PV+ interneurons in conjunction with recurrent connectivity among the principal neurons can reproduce slow ramping signals, while plasticity of excitatory synapses on SOM+ interneurons can explain the acceleration of these signals in trained animals. Together, our data reveal that local inhibitory neurons play distinct roles in controlling task-dependent preparatory ramping signals when MOs neurons integrate external inputs during motor planning. HighlightsO_LIPrincipal neurons in MOs show slow preparatory membrane potential and firing rate ramps preceding the onset of spontaneous, self-paced running periods. C_LIO_LIIn animals trained to perform a goal-directed task, both membrane potential and spike ramps are faster and larger in amplitude. C_LIO_LIInactivation of PV+ interneurons disinhibits MOs principal neurons and increases the amplitude of membrane potential ramps, while inactivation of SOM+ interneurons abolishes membrane potential ramps. C_LIO_LIOur modeling results suggest that the concerted action of external inputs and local inactivation shapes task-dependent preparatory motor signals in MOs neurons. C_LI

neuroscience↗

bioRxiv2021

A synaptic novelty signal in the dentate gyrus supports switching hippocampal attractor networks from generalization to discrimination

Episodic memory formation and recall are complementary processes that put conflicting requirements on neuronal computations in the hippocampus. How this challenge is resolved in hippocampal circuits is unclear. To address this question, we obtained in vivo whole-cell patch-clamp recordings from dentate gyrus granule cells in head-fixed mice trained to explore and distinguish between familiar and novel virtual environments. We find that granule cells consistently show a small transient depolarization of their membrane potential upon transition to a novel environment. This synaptic novelty signal is sensitive to local application of atropine, indicating that it depends on metabotropic acetylcholine receptors. A computational model suggests that the observed transient synaptic response to novel environments may lead to a bias in the granule cell population activity, which can in turn drive the downstream attractor networks to a new state, thereby favoring the switch from generalization to discrimination when faced with novelty. Such a novelty-driven cholinergic switch may enable flexible encoding of new memories while preserving stable retrieval of familiar ones.

neuroscience↗

bioRxiv2019

The hippocampus as a perceptual map: neuronal and behavioral discrimination during memory encoding

The hippocampus is thought to encode similar events as distinct memory representations that are used for behavioral decisions. Where and how this "pattern separation" function is accomplished in the hippocampal circuit, and how it relates to behavior, is still unclear. Here we perform in vivo 2-photon Ca2+ imaging from hippocampal subregions of head-fixed mice performing a virtual-reality spatial discrimination task. We find that population activity in the input region of the hippocampus, the dentate gyrus, robustly discriminates small changes in environments, whereas spatial discrimination in CA1 reflects the behavioral performance of the animals and depends on the degree of differences between environments. Our results demonstrate that the dentate gyrus amplifies small differences in its inputs, while downstream hippocampal circuits will act as the final arbiter on this decorrelated information, thereby producing a "perceptual map" that will guide behaviour.

neuroscience↗