title: Heterogeneous reallocation of presynaptic efficacy in recurrent excitatory circuits adapting to inactivity.
abstract: Recurrent excitatory circuits face extreme challenges in balancing efficacy and stability. We recorded from CA3 pyramidal neuron pairs in rat hippocampal slice cultures to characterize synaptic and circuit-level changes in recurrent synapses resulting from long-term inactivity. Chronic tetrodotoxin treatment greatly reduced the percentage of connected CA3-CA3 neurons, but enhanced the strength of the remaining connections; presynaptic release probability sharply increased, whereas quantal size was unaltered. Connectivity was decreased in activity-deprived circuits by functional silencing of synapses, whereas three-dimensional anatomical analysis revealed no change in spine or bouton density or aggregate dendrite length. The silencing arose from enhanced Cdk5 activity and could be reverted by acute Cdk5 inhibition with roscovitine. Our results suggest that recurrent circuits adapt to chronic inactivity by reallocating presynaptic weights heterogeneously, strengthening certain connections while silencing others. This restricts synaptic output and input, preserving signaling efficacy among a subset of neuronal ensembles while protecting network stability.
authors.affiliation: Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ananya
authors.initials: A
authors.lastname: Mitra
authors.forename: Siddhartha S
authors.initials: SS
authors.lastname: Mitra
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tsien
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology*; D000779:Anesthetics, Local / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D055592:Biophysical Phenomena; D005576:Colforsin / Q000494:pharmacology; D051360:Cyclin-Dependent Kinase 5 / Q000378:metabolism; D004558:Electric Stimulation; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects / Q000502:physiology*; D025461:Feedback, Physiological; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology; D009412:Nerve Fibers / Q000502:physiology; D009415:Nerve Net / Q000187:drug effects / Q000502:physiology; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009474:Neurons / Q000166:cytology*; D009924:Organ Culture Techniques; D018408:Patch-Clamp Techniques; D017729:Presynaptic Terminals / Q000187:drug effects / Q000502:physiology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077546:Roscovitine; D013569:Synapses / Q000187:drug effects / Q000502:physiology*; D013779:Tetrodotoxin / Q000494:pharmacology
chemical_list: D000779:Anesthetics, Local; D009419:Nerve Tissue Proteins; D047428:Protein Kinase Inhibitors; D011687:Purines; C089495:neuronal Cdk5 activator (p25-p35); D000077546:Roscovitine; D005576:Colforsin; D013779:Tetrodotoxin; D051360:Cyclin-Dependent Kinase 5