Biology subjects

Ittner, A.

Publications and source records attributed to Ittner, A..

3 recordsLinked to original sources

bioRxiv2026

The mood stabilizer lithium alters behaviour and physiology via the gut brain axis.

Lithium, introduced 75 years ago by John Cade1, remains the most effective mood stabilizer for bipolar disorder2. Lithium is proposed to modulate an array of cellular pathways, many ubiquitous to all cells, with pleiotropic roles unlinked to bipolar disorder or lithium responsiveness in genome-wide association studies3,4. These mechanisms cannot explain lithiums specific effects on mood and behaviour. We demonstrate that lithiums primary action is in the periphery, not in the brain itself. Lithium acts in the gut to trigger behavioural and physiological changes, akin to those associated with a torpor-like state, that protect individuals from ingested toxins. Lithium activates gastrointestinal enterochromaffin (EC) cells via their Trpm2 cation channels to modulate afferent vagal and area postrema inputs to the brain. Eliminating these inputs by focal brain lesions eliminates lithiums effects, as does ablation of EC cells or their Trpm2 expression. Lithiums Trpm2-dependent activation of EC cells also occurs in human gut tissue, providing translational relevance for our discovery. These findings challenge the prevailing perception that lithium acts directly on the brain. Via a previously unsuspected gut-brain pathway, lithium engages brain circuitry that reduces arousal and interaction with the external world, therapeutic goals in the manic phase of bipolar disorder.

neuroscience↗

bioRxiv2025

Tau controls NMDA receptor trafficking during homeostatic synaptic plasticity

Homeostatic synaptic plasticity is essential for maintaining stable neural circuit function by preventing excessive neuronal excitation or inhibition. Chronic perturbation of neuronal activity triggers a compensatory modulation of the number of -amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) and N-methyl-D-aspartate (NMDA) glutamate receptors at the excitatory synapses. Previous research has primarily focused on AMPA receptors, yet the molecular mechanisms regulating the trafficking of NMDA receptors during homeostatic synaptic scaling remain unclear. Here we identify the microtubule-associated protein Tau as an essential molecule that mediates the synaptic upscaling of GluN2B-containing NMDA receptors during prolonged synaptic inactivity. Chronic activity blockade increases Tau phosphorylation at Ser-235 by cyclin-dependent kinase 5 (Cdk5), enhancing its interaction with and retention of active Fyn tyrosine kinase in the postsynaptic compartment. This promotes the phosphorylation of GluN2B at Tyr-1472, subsequently stabilising the expression of NMDA receptors on the neuronal plasma membrane. Finally, we showed that Tau pathology and disease-associated mutations in Tau and the GluN2B carboxyl-terminal tail disrupt the homeostatic synaptic upscaling of NMDA receptors following chronic neuronal silencing. Together, our findings identify a physiological role for Tau in homeostatic synaptic plasticity, the perturbation of which can lead to neuronal hyperexcitation, seizures and excitotoxic cell death.

neuroscience↗

bioRxiv2023

Remote memory engrams are controlled by encoding-specific tau phosphorylation

The engram represents the physical trace that encodes a specific memory and enables its recall 1-4. Functional failure of the engram is linked to the progressive memory decline in Alzheimers disease 5. However, it is unknown whether the microtubule-associated protein tau, a central factor in Alzheimers 6,7, has a direct function in the engram. Here, we demonstrate that tau and encoding-associated tau phosphorylation are critical for robust remote memory engrams. Tau is required specifically during memory formation for remote, yet not proximal recall in memory paradigms in mice. Controlled expression of tau exclusively during memory entrainment is necessary and sufficient to restore remote memory deficits in tau knockout mice. Tau is phosphorylated at specific sites during encoding. Gene editing to ablate site-specific phosphorylation at threonine-205 (T205) lowers precision of engram cell recruitment and precludes efficient remote recall. Vector-based engineering of engram cells reveals that T205 phosphorylation of tau is required to engrain memory for recall at remote timepoints. Notably, in the absence of tau, memory is recalled from latency by direct optogenetic activation of engram cells at distal time points but not when natural cues are used, revealing an association-specific gatekeeper function of tau during encoding. Our work delineates a physiologic role of site-specific tau phosphorylation at the inception of episodic memory to support an enduring engram and enable efficient remote recall. Thus, encoding-associated phosphorylation of tau is proximal to the elusive substrate of remote memory and may connect to the basis of amnesia in Alzheimers disease.

neuroscience↗