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.
Abstract
The hippocampus forms memories of our experiences in populations of coactive pyramidal neurons (PNs)1–3. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus–CA3/CA2 circuit of the hippocampus precisely control PN activity through mossy fibre-dependent feedforward inhibition4–11. PV INs coordinate experience-dependent changes in their intrinsic excitability, synaptic connectivity, physiology and plasticity properties9,12–15—referred to here as experience-dependent PV IN plasticity—to regulate PN activity. PV IN impairments in early life, when neural circuitry is highly sensitive to experience, are thought to result in network hyperexcitability, seizures and impaired cognition, which are hallmarks of neurodevelopmental disorders (NDDs)16–18. Here we designed an input-specific translatome screen to identify regulators of experience-dependent PV IN plasticity genes (XPGs) in the CA3/CA2 subregion of adult hippocampus. We demonstrate that a substantial proportion of upregulated candidate XPGs exhibit haploinsufficiency in autism spectrum disorder, epilepsies, bipolar disorder and schizophrenia, which suggests that there is impaired experience-dependent PV IN plasticity in NDDs. In proof-of-concept experiments, targeted upregulation of a candidate XPG, the homeobox gene Meis2 (ref. 19), in CA3/CA2 PV INs in an NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity. Moreover, ensemble and sharp-wave ripple properties and cognition were improved, and seizures were suppressed. Thus, 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.
ABSTRACT Aims Absence seizures, characterized by spike‐and‐wave discharges (SWDs), are mediated by reciprocal thalamocortical interactions; however, the contribution of developing inhibitory networks to SWDs remains unclear. We investigated the developmental trajectory of inhibitory interneurons in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) by analyzing their distribution across postnatal development in the somatosensory (S1) and motor (M1) cortices, the hippocampus, and striatum. Methods The neurodevelopmental trajectory of parvalbumin‐positive (PV+) and somatostatin‐positive (SST+) interneurons was quantified at three critical stages: postnatal day 14 (P14), when SWDs were not yet observed, P21 when immature SWDs appear, and adulthood (P90), when mature SWDs are established. Wistar rats served as controls. Brain sections were processed immunohistochemically to quantify interneuron density. Results PV+ interneuron density across S1 and M1 was significantly higher in GAERS at P14 than control. However, this difference was not maintained at P21 and adults. Conversely, SST+ interneurons exhibited a delayed increase in M1. GAERS displayed higher PV+ interneuron density in the dentate gyrus and CA1 at P14, whereas SST+ interneuron density remained unchanged across hippocampal subfields. Striatal PV+ and SST+ interneurons increased at later developmental stages, suggesting altered inhibition in basal ganglia. Conclusion These findings demonstrate a temporally dynamic and region‐specific reorganization of interneurons in GAERS that may underlie absence epileptogenesis.
N. Çarçak, Elif Tuğçe Erdeve, Courtney J. Wright et al.· CNS Neuroscience & Therapeut...· 0 citations
Sensory processing deficits in schizophrenia have been linked to dysfunction of cortical inhibitory interneurons, particularly parvalbumin-expressing (PV+) populations. NMDA receptor hypofunction during development is known to disrupt interneuron maturation, but its long-term impact on visual cortex circuitry and the potential for experience-dependent modulation in adulthood remain unclear. Here, we examined the effects of early postnatal N-methyl-D-aspartate (NMDA) receptor blockade with MK-801 on the number of PV+ and somatostatin-expressing (SST+) interneurons in the primary visual cortex (V1) and assessed whether environmental enrichment (EE) in adulthood modulates these alterations by analyzing molecular changes using Western blot. Male Long–Evans rats received MK-801 (0.5 mg/kg) or saline from postnatal day 10–20, followed by EE exposure from P55–73. Stereological analyses revealed a marked reduction of PV-immunoreactive cells in layers II/III and IV, while SST+ populations were largely preserved. EE increased the number of PV-immunoreactive cells across groups, and modestly enhanced SST+ cells in layer IV, although no treatment × housing interaction was detected, indicating a general enrichment-related effect. At the molecular level, MK-801 reduced expression of the NMDA receptor subunit NR1 and increased Akt phosphorylation, whereas EE enhanced PSD95 expression, ERK phosphorylation, and GABAA β2/3 subunit levels, without increasing NR1 levels. These findings indicate that early NMDA receptor hypofunction induces long-lasting, subtype-specific alterations in inhibitory circuitry in V1. EE in adulthood engages molecular pathways associated with synaptic plasticity and modulates interneuron immunoreactivity, suggesting that inhibitory circuits retain some capacity for experience-dependent remodeling despite persistent receptor-level deficits.
A. Murueta-Goyena, N. Ortuzar, S. Bulnes et al.· Brain Structure and Function· 0 citations
It is shown that robust and reversible plasticity can be induced in adult mice by prolonged dark exposure (DE) and light reintroduction (LRx) and that robust plasticity is engaged at thalamocortical synapses in adults by visual deprivation, a non-invasive manipulation with therapeutic potential.
S. Murase, Daniel Severin, Andrew Pranger et al.· bioRxiv· 0 citations
The functional integrity of the medial prefrontal cortex (mPFC) depends on the accurate integration of synaptic inputs via the dynamic interplay between pyramidal cells (PCs) and GABAergic interneurons. In this comparative study, we report how aging alters the electrophysiological profiles of layer 5 PCs and local interneurons in the rat mPFC. Relative to 2-month-old rats, 24 ± 2-month-old acute brain slices containing the prelimbic area of mPFC exhibited changes in the passive and active membrane properties governing neuronal excitability. Whole-cell patch-clamp recordings showed reduced firing frequency in PCs and increased firing frequency in interneurons. Analysis of ionic conductances revealed decreased voltage-gated sodium current amplitude in PCs, whereas interneurons exhibited decreased potassium current amplitudes. Extracellular recordings further identified network-level impairments with aging, including reduced population spike amplitude and diminished gain, indicating decreased synaptic recruitment. Short-term plasticity was selectively affected: at 10 and 30Hz, aging increased the decay time constant and attenuated synaptic depression by preserving higher response amplitudes, while responses to 50Hz stimulation remained unchanged. By recording both neuronal types within the same experimental and anatomical framework, this study enabled a unified interpretation of how cell-type-specific aging adaptations emerge within a shared microenvironment. Overall, aging differentially disrupts excitability and ionic mechanisms in pyramidal and interneuron populations, leading to impaired synaptic integration and altered short-term plasticity in mPFC microcircuits. Collectively, these findings suggest that disrupted synaptic integration and intrinsic neuronal function in the aged neocortex may contribute to age-related cognitive decline.
Vladimir A. Martínez-Rojas, Diana A. Rosas-García, Gabriela Rocha-Botello et al.· Mechanisms of Ageing and Dev...· 0 citations
Evidence suggesting that L3PN morphology and physiology differ significantly across PFC, PPC and V1 in primates is reviewed, suggesting a primate-enhanced regional variability that may be the substrate for area-specific L3PN vulnerability in schizophrenia.
G. González-Burgos, R. Benavides-Piccione, A. Neef et al.· Biological Psychiatry· 0 citations
The pathophysiology of depression involves multiple biological processes, including circuit dysfunction and impaired neuroplasticity, yet an integrative view linking these processes remains elusive. Here, we identify a convergent circuit for antidepressant response and plasticity modulation. We demonstrate that chemogenetic activation of the infralimbic cortex (IL) exerts rapid antidepressant-like effects across multiple behavioral domains in a mouse model of stress-induced depression. IL stimulation exerts top-down control over the hippocampus, enhancing structural plasticity, restoring long-term potentiation deficits and improving state-dependent network dynamics in the ventral hippocampus (vHIPP). We identify the thalamic nucleus reuniens (RE) as a necessary mediator of these effects. Notably, direct inhibition of RE, its inputs from IL or projections to vHIPP, blocks both IL stimulation-induced antidepressant response and the therapeutic and neuroplastic effects of ketamine. Our findings demonstrate that the functional IL → RE→vHIPP circuit plays a central role in the antidepressant response, linking circuit activity, hippocampal plasticity, and depressive-like behaviors. Neural mechanisms underlying depression are not fully understood. This study identifies a prefrontal–thalamic–hippocampal circuit that links antidepressant-like behavior with restored neural plasticity and is required for ketamine’s behavioral and neuroplastic effects in mice.
M. Veleanu, Louise Schuberth, Antje Kilias et al.· Nature Communications· 0 citations
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