Alfredo Kirkwood

Experience reshapes cortical circuits, yet plasticity is tightly gated—high during early critical periods and increasingly constrained with maturation. Later in life, aging and Alzheimer’s disease (AD) create a growing demand to restrain network hyperactivity. Across these contexts, excitatory drive onto parvalbumin-positive fast-spiking interneurons (PVs)—shaped by synaptic organizers such as NPTX2—offers a control point for tuning inhibitory tone while preserving fast, precise inhibition. We outline the cellular and synaptic specializations that make PVs powerful regulators of network excitability, then synthesize evidence from visual cortex suggesting that critical period termination reflects the loss of plasticity at principal neuron→PV inputs. Finally, we extend this framework to aging and AD, where medial temporal lobe hyperactivity and early PV dysfunction coincide with NPTX2 dysregulation, suggesting that restoring excitatory recruitment of PVs may help stabilize circuits and prevent cognitive decline.

Long-term potentiation (LTP), the best-characterized form of Hebbian synaptic plasticity, is well known to be under strong circadian regulation. In mice and rats, both nocturnal species, most studies indicate that LTP in the hippocampal CA1 region is more robust when induced during the dark phase. Our examination of the underlying mechanisms at the CA3→CA1 synapse in mice of all sexes indicates that the capacity to support LTP does not differ between the light and dark phases of the 24 h day. Instead, the magnitude of theta burst stimulation-induced LTP (TBS-LTP) correlates with daily fluctuations in the ratio of synaptic excitation to inhibition (E/I ratio): both the E/I ratio and TBS-LTP are higher during the dark phase. On the other hand, LTD induced with low-frequency stimulation did not change across the circadian cycle. Consistent with a causal relationship between the E/I ratio and TBS-LTP, blockade of inhibition abolishes the light–dark difference in TBS-LTP induction. Likewise, pairing-induced LTP, which is not constrained by inhibitory recruitment, does not differ between cycles. Supporting this, in the APP/PS1 model of AD neither the E/I ratio nor TBS-LTP varies across the light–dark cycle, despite preserved circadian regulation of locomotor activity. Finally, we made the intriguing observation that these daily oscillations reverse direction after puberty in WT mice, shifting from being larger in the dark cycle of 2-month-old mice to being larger in the light cycle in 8-month-old mice. This developmental switch may reflect an age-dependent reorganization of circadian control over hippocampal plasticity.

The preservation of cognitive function during aging remains a key challenge in neuroscience. In this study, we applied an integrative approach, combining behavioral assays with neurophysiological recordings, to investigate hippocampal circuit integrity. We used Octodon degus , a rodent with exceptional longevity (up to 10 years in laboratory conditions), as a natural model of aging and neurodegenerative disease such as Alzheimer. To assess agerelated cognitive changes, we employed three behavioral tasks: Novel Object Recognition (NOR), Open Field (OF), and the Burrowing Test (BT). The BT reflects Activities of Daily Living (ADLs) and is based on species-typical spontaneous burrowing behavior, which has been linked to neurodegenerative markers in degus. We also performed multielectrode electro-physiological recordings to assess GABAergic function in the hippocampus. Aged degus with high BT performance (classified as good burrowers, or GB) showed robust hippocampal activity, especially in the CA3 region, a key hub for signal integration and memory encoding. In contrast, degus with poor BT performance (bad burrowers, or BB) exhibited reduced spontaneous hippocampal activity, suggesting potential compensation via GABA-independent synaptic mechanisms. Altogether, our findings suggest that preserved GABAergic function supports cognitive resilience in aging degus. These results offer new insights into the neural mechanisms underlying healthy cognitive aging and may inform future strategies for preventing or mitigating neurodegeneration.

Summary: Age constrains plasticity at inputs from first order thalamic nuclei to the cortex, endowing stability to ascending, feed-forward projections. However, here we show that prolonged visual deprivation can induce robust and reversible plasticity at thalamocortical synapses in layer 4 pyramidal neurons in the adult mouse primary visual cortex. The plasticity engaged by prolonged visual deprivation is non-homeostatic and mediated by changes in presynaptic function.

Monocular deprivation (MD) causes an initial decrease in synaptic responses to the deprived eye in juvenile mouse primary visual cortex (V1) through Hebbian long-term depression (LTD). This is followed by a homeostatic increase, which has been attributed either to synaptic scaling or to a slide threshold for Hebbian long-term potentiation (LTP) rather than scaling. We therefore asked in mice of all sexes whether the homeostatic increase during MD requires GluN2B-containing NMDA receptor activity, which is required to slide the plasticity threshold but not for synaptic scaling. Selective GluN2B blockade from 2–6 d after monocular lid suture prevented the homeostatic increase in miniature excitatory postsynaptic current (mEPSC) amplitude in monocular V1 of acute slices and prevented the increase in visually evoked responses in binocular V1 in vivo.The decrease in mEPSC amplitude and visually evoked responses during the first 2 d of MD also required GluN2B activity. Together, these results support the idea that GluN2B-containing NMDA receptors first play a role in LTD immediately following eye closure and then promote homeostasis during prolonged MD by sliding the plasticity threshold in favor of LTP.

SynGAP is an abundant synaptic GTPase-activating protein (GAP) critical for synaptic plasticity, learning, memory, and cognition. Mutations in SYNGAP1 in humans result in intellectual disability, autistic-like behaviors, and epilepsy. Heterozygous Syngap1 -knockout mice display deficits in synaptic plasticity, learning, and memory and exhibit seizures. It is unclear whether SynGAP imparts structural properties at synapses independently of its GAP activity. Here, we report that inactivating mutations within the GAP domain do not inhibit synaptic plasticity or cause behavioral deficits. Instead, SynGAP modulates synaptic strength by physically competing with the AMPA-receptor-TARP excitatory receptor complex in the formation of molecular condensates with synaptic scaffolding proteins. These results have major implications for developing therapeutic treatments for SYNGAP1 -related neurodevelopmental disorders.