Biology subjects

Flores, J. C.

Publications and source records attributed to Flores, J. C..

3 recordsLinked to original sources

bioRxiv2026

Synaptic Plasticity as a Function of the Temporal Derivative

A major outstanding question in neuroscience is whether the neocortex uses the same powerful learning algorithm as current AI models: error backpropagation. One way this could be accomplished is as a function of the temporal derivative (i.e., differences in neural activity states over time), which can closely approximate the backpropagated error gradient. We tested the hypothesis that the direction of synaptic plasticity is a function of the temporal derivative in synaptic activity over the course of a 200 ms (5 Hz) theta cycle. Using mouse hippocampal slices, we drove presynaptic activity across the two 100 ms halves of a 200 ms window at either 25 Hz or 50 Hz, combined with corresponding low and high magnitudes of postsynaptic depolarization, testing all four 2x2 combinations of these low and high activity levels, while measuring the resulting effects on synaptic efficacy (as measured by EPSP amplitude to standard test probes). Consistent with the computational hypothesis, a positive temporal derivative (low to high) resulted in LTP (increased synaptic strength), while a negative temporal derivative (high to low) resulted in LTD. Critically, both no-change conditions (stable low or high across 200 ms) resulted in no net synaptic change, even though the high no-change condition had the highest overall synaptic activity levels. Possible biochemical mechanisms that could support these results are discussed.

neuroscience↗

bioRxiv2024

A synapse-specific refractory period for plasticity at individual dendritic spines

How newly formed memories are preserved while brain plasticity is ongoing has been a source of debate. One idea is that synapses which experienced recent plasticity become resistant to further plasticity, a type of metaplasticity often referred to as saturation. Here, we probe the local dendritic mechanisms that limit plasticity at recently potentiated synapses. We show that recently potentiated individual synapses exhibit a synapse-specific refractory period for further potentiation. We further found that the refractory period is associated with reduced postsynaptic CaMKII signaling; however, stronger synaptic activation only partially restored the ability for further plasticity. Importantly, the refractory period is released after one hour, a timing that coincides with the enrichment of several postsynaptic proteins to pre-plasticity levels. Notably, increasing the level of the postsynaptic scaffolding protein, PSD95, but not of PSD93, overcomes the refractory period. Our results support a model in which potentiation at a single synapse is sufficient to initiate a synapse-specific refractory period that persists until key postsynaptic proteins regain their steady-state synaptic levels. Significance StatementA refractory period in which newly modified synaptic connections are unable to undergo further plasticity is a proposed mechanism through which newly formed memories can be preserved at the synaptic level while brain plasticity is ongoing. Here, we provide new insights into the spatiotemporal signaling mechanisms that regulate the establishment and maintenance of a refractory period for plasticity at individual excitatory synapses in the hippocampus, a region of the brain vital for learning and memory. Our results have implications in the identification of molecular targets that could serve to improve learning outcomes associated with disease.

neuroscience↗

bioRxiv2020

Molecular Mechanisms of Non-ionotropic NMDA Receptor Signaling

Structural plasticity of dendritic spines is a key component of the refinement of synaptic connections during learning. Recent studies highlight a novel role for the NMDA receptor (NMDAR), independent of ion flow, in driving spine shrinkage and LTD. Yet little is known about the molecular mechanisms that link conformational changes in the NMDAR to changes in spine size and synaptic strength. Here, using two-photon glutamate uncaging to induce plasticity in hippocampal CA1 neurons from mice and rats, we demonstrate that p38 MAPK is required downstream of conformational NMDAR signaling to drive both spine shrinkage and LTD at individual dendritic spines. In a series of pharmacological and molecular genetic experiments, we identify key components of the non-ionotropic NMDAR signaling pathway driving dendritic spine shrinkage, including the interaction between NOS1AP and nNOS, nNOS enzymatic activity, activation of MK2 and cofilin, and signaling through CaMKII. Our results represent a large step forward in delineating the molecular mechanisms of non-ionotropic NMDAR signaling that drive the shrinkage and elimination of dendritic spines during synaptic plasticity.

neuroscience↗