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Synaptic plasticity is believed to be a key physiological mechanism for learning. It is well established that it depends on pre- and postsynaptic activity. However, models that rely solely on pre- and postsynaptic activity for synaptic changes have, so far, not been able to account for learning complex tasks that demand credit assignment in hierarchical networks. Here we show that if synaptic plasticity is regulated by high-frequency bursts of spikes, then pyramidal neurons higher in a hierarchical circuit can coordinate the plasticity of lower-level connections. Using simulations and mathematical analyses, we demonstrate that, when paired with short-term synaptic dynamics, regenerative activity in the apical dendrites and synaptic plasticity in feedback pathways, a burst-dependent learning rule can solve challenging tasks that require deep network architectures. Our results demonstrate that well-known properties of dendrites, synapses and synaptic plasticity are sufficient to enable sophisticated learning in hierarchical circuits.
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http://dx.doi.org/10.1038/s41593-021-00857-x | DOI Listing |
EMBO J
September 2025
Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan.
During a critical period of postnatal brain development, neural circuits undergo significant refinement coincident with widespread alternative splicing of hundreds of genes, which undergo altered splice site selection for the generation of isoforms essential for synaptic plasticity. Here, we reveal that neuronal activity-dependent phosphorylation of paxillin at its serine 119 (p-paxillin) acts as a molecular switch in the nucleus for the control of alternative splicing during this period. We show that following NMDA receptor activation, nuclear p-paxillin is recruited to nuclear speckles, where it interacts with splicing factors, such as U2AFs.
View Article and Find Full Text PDFNeurol Res
September 2025
Department of Physiology, All India Institute of Medical Sciences (AIIMS), New Delhi, India.
Background: Spinal Cord Injury (SCI) leads to partial or complete sensorimotor loss because of the spinal lesions caused either by trauma or any pathological conditions. Rehabilitation, one of the therapeutic methods, is considered to be a significant part of therapy supporting patients with spinal cord injury. Newer methods are being incorporated, such as repetitive Transcranial Magnetic Stimulation (rTMS), a Non-Invasive Brain Stimulation (NIBS) technique to induce changes in the residual neuronal pathways, facilitating cortical excitability and neuroplasticity.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
September 2025
Vanderbilt Brain Institute, Vanderbilt University, Nashville, TN 37240.
Major depressive disorder affects millions worldwide, yet current treatments require prolonged administration. In contrast, ketamine produces rapid antidepressant effects by blocking spontaneous N-Methyl-D-Aspartate (NMDA) receptor signaling, which lifts the suppression of protein synthesis and triggers homeostatic synaptic plasticity. Here, we identify a parallel signaling pathway involving metabotropic glutamate receptor 5 (mGluR5) that promotes rapid antidepressant-like effects.
View Article and Find Full Text PDFProc Natl Acad Sci U S A
September 2025
Institut de Biologie de l'Ecole Normale Supérieure, Ecole Normale Supérieure, Université Paris Sciences et Lettres, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Paris 75005, France.
Excitatory glycine receptors (eGlyRs), composed of the glycine-binding NMDA receptor subunits GluN1 and GluN3A, have recently emerged as a novel neuronal signaling modality that challenges the traditional view of glycine as an inhibitory neurotransmitter. Unlike conventional GluN1/GluN2 NMDARs, the distribution and role of eGlyRs remain poorly understood. Here, we show that eGlyRs are highly enriched in the ventral hippocampus (VH) and confer distinct properties on this brain region.
View Article and Find Full Text PDFPsychopharmacology (Berl)
September 2025
División de Neurociencias, Instituto de Fisiología Celular, Universidad Nacional Autónoma de México, Ciudad Universitaria, Mexico City, 04510, Mexico.
Rationale: One of the earliest changes associated with Alzheimer's disease (AD) is the loss of catecholaminergic terminals in the cortex and hippocampus originating from the Locus Coeruleus (LC). This decline leads to reduced catecholaminergic neurotransmitters in the hippocampus, affecting synaptic plasticity and spatial memory. However, it is unclear whether restoring catecholaminergic transmission in the terminals from the LC may alleviate the spatial memory deficits associated with AD.
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