Visual deprivation in adulthood engages presynaptic plasticity of thalamocortical synapses

Sensory experience drives glutamate spillover, presynaptic LTP and functional connectome remodeling in the barrel cortex

Royal Netherlands

Procognitive restoration of PV neuron plasticity in neurodevelopmental disorders

An input-specific translatome screen is designed to identify regulators of experience-dependent PV IN plasticity genes (XPGs) in the CA3/CA2 subregion of adult hippocampus and shows that experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.

SRGAP2 limits experience-dependent structural synaptic plasticity in adult cortical circuits

In cortical circuits, synaptic plasticity involves either changes in the weight of pre-existing synapses, referred to as functional synaptic plasticity, or synapse formation and elimination, referred to as structural synaptic plasticity. Experience-dependent structural synaptic plasticity is prominent in juvenile cortical circuits during critical periods of development but drastically decreases in adult cortical circuits. The molecular mechanisms limiting experience-dependent structural synaptic plasticity in adult cortical circuits remain largely unknown. During development, the postsynaptic protein SRGAP2 limits the formation of both excitatory (E) and inhibitory (I) synapses in cortical pyramidal neurons (CPNs) and promotes their maturation. SRGAP2 expression is maintained throughout adulthood but its synaptic function in the adult cortex has not been explored. Using longitudinal 2-photon (2P) imaging of dendritic spine dynamics in layer 2/3 CPNs and found that this form of sensory deprivation induces a striking increase in structural synaptic plasticity favoring spine formation in adult constitutive SRGAP2+/- mice, in contrast to wild-type adult mice, where whisker trimming does not induce significant structural synaptic plasticity. Using conditional, cell-type specific, deletion of SRGAP2, we demonstrate that this experience-dependent structural synaptic plasticity requires both of SRGAP2 in expression L2/3 CPNs and in microglia. We previously demonstrated that the human-specific paralogs SRGAP2B/C inhibit all known functions of SRGAP2, phenocopying SRGAP2 haploinsufficiency, our results suggest that SRGAP2B/C might endow increased levels of experience-dependent structural synaptic plasticity to human pyramidal neurons in adult cortical circuits.

Activity-Dependent Changes in Axonal Action Potential Latency Coordinated with Synaptic Potentiation in Individual Hippocampal Neurons

Neural plasticity enables the nervous system to adapt its structure and function in response to experience. Although synaptic plasticity is a central cellular mechanism underlying learning and memory, action potential propagation along axons is also subject to plastic regulation and critically shapes neural computation. However, how these distinct forms of plasticity are coordinated within individual neurons remains poorly understood. Here, we simultaneously monitored synaptic responses and antidromically evoked action potentials in hippocampal CA1 pyramidal neurons from male rats using whole-cell recordings. High-frequency stimulation reliably induced long-term potentiation (LTP) and was accompanied by a delayed yet transient reduction in antidromic action potential latency. The magnitude of latency shortening correlated with the degree of synaptic potentiation across multiple post-high-frequency stimulation time windows, including a late phase during which synaptic responses remained persistently elevated. Blocking the induction of LTP by intracellular Ca2+ chelation or NMDA receptor antagonism abolished latency shortening, indicating a dependence on LTP-related signaling pathways. Notably, the temporal profile of latency modulation depended on the site of axonal stimulation: latency shortening emerged earlier at proximal sites and was delayed at more distal sites, suggesting the propagation or accumulation of plasticity-related signals along an axon. Dual-site axonal stimulation within single neurons further demonstrated that action potential latency changes differed across axonal locations. Together, these findings demonstrate that synaptic potentiation is accompanied by spatially and temporally organized latency changes, revealing an additional layer of activity-dependent plasticity within individual neurons.

A reactivated thalamocortical plasticity window promotes learning and is reshaped by experience

Adult sensory loss can reactivate critical-period-like thalamocortical plasticity, but whether this reactivation defines a temporally gated circuit state that facilitates learning and is reciprocally shaped by experience remains unknown. Here we define its in vivo trajectory and functional consequences in adult mouse barrel cortex. Infraorbital nerve transection opened a transient window of enhanced layer 4 thalamocortical gain. Training during this window lowered whisker-detection thresholds and promoted learning by accelerating the transition to stable performance. Local GluN2B blockade prevented both cortical potentiation and the learning advantage, linking critical-period-associated plasticity mechanisms to adaptive behavior in the adult brain. Neuropixels recordings showed that weak inputs preferentially increased neuronal responses, whereas strong inputs produced sharper temporal coding. The relationship was reciprocal: experience reshaped the trajectory of this circuit state, with training before the normal peak advancing the emergence of potentiation, training during the active window prolonging the potentiated state, and training after closure failing to reinstate potentiation. State prolongation accompanied more persistent sensory memory. These findings establish a reciprocal, timing-dependent interaction between endogenous plasticity and experience, revealing a general principle by which adult circuits can convert transient plastic potential into adaptive behavioral change and informing strategies that align training with periods of heightened plasticity.