It is demonstrated that mTORC1 dysregulation in parvalbumin-expressing (PV) interneurons drives heightened tactile exploration and defensiveness in adult mutant mice, and the interplay between mTORC1 signaling and sensory experience in PV cells regulates their connectivity, and contributes to the proper development of tactile and social behavior.
Abstract
Sensory abnormalities are core features of neurodevelopmental disorders, including autism. Although interneuron dysfunction is hypothesized to contribute to these deficits, the underlying mechanisms remain unclear. Here, we demonstrate that mTORC1 dysregulation in parvalbumin-expressing (PV) interneurons drives heightened tactile exploration and defensiveness. These behavioral changes coincide with whisker-evoked cortical responses characterized by increased power but degraded temporal precision. Excitatory inputs to PV cells, their intrinsic excitability and in vivo firing rate during tactile exploration are reduced, suggesting that mutant PV cells are hypoactive. Whisker trimming restricted to the third postnatal week prevented mTORC1 hyperactivation, PV cell input and output connectivity deficits as well as abnormal tactile cortical responses and behavior in adult mutant mice. Further, this manipulation rescued sociability deficits. Altogether, these data suggest that the interplay between mTORC1 signaling and sensory experience in PV cells regulates their connectivity, and contributes to the proper development of tactile and social behavior.
Neural circuits in the spinal cord are composed of diverse populations of interneurons that play crucial roles in shaping motor output. However, the extent of interneuron heterogeneity and how this diversity relates to functional aspects of movement remain unclear. Here, through a focus on mouse spinal V1 interneurons, we show that loss of the V1 transcription factor En1 selectively disrupts the frequency of rhythmic locomotor output but does not disrupt flexion/extension limb movement, thereby decoupling two key functional roles ascribed to this neuronal population. To investigate the cellular basis of these deficits, we generated a single-nucleus transcriptomic atlas of V1 interneurons across postnatal development. Our analysis reveals age-dependent transcriptional changes while also demonstrating that their core molecular taxonomy perdures into adulthood. Notably, En1 deficiency selectively perturbed a single subset of V1Pou6f2 interneurons, thereby identifying a possible cellular substrate for influencing locomotor speed. Beyond serving as a molecular resource, our study highlights how deep neuronal profiling provides an entry point for understanding the multifunctional nature of heterogeneous interneuron populations. This study leverages transcriptomic profiling of spinal V1 interneurons to understand how they contribute to movement. By genetically targeting and manipulating these neurons, the authors decouple locomotor speed and limb flexion phenotypes, suggesting these key elements of motor control may be governed by different subsets of V1 interneurons.
Alexandra J. Trevisan, Ka-Tie Han, Phillip Chapman et al.· Nature Communications· 0 citations
These findings identify Dlx5/6 as regulators of adult PV interneuron stability, linking extracellular matrix homeostasis to synaptic organization and cortical network dynamics, and provides a new mechanistic framework connecting Dlx5/6 function to PV-related pathological phenotypes, including neuropsychiatric disorders.
BACKGROUND
Sensory processing dysfunction is linked to emotional dysregulation and anxiety in humans. While tactile deprivation is known to impair dorsal hippocampal functions (spatial memory and learning), its impact on the cytoarchitecture of limbic regions central to emotional processing remains poorly understood.
METHODS
Adult CD-1 mice (postnatal day 50) underwent bilateral infraorbital nerve transection (Tactile Deprivation, TD) or sham surgery. Four weeks later, anxiety-like behavior was assessed using the Open Field (OFT), Elevated Plus Maze (EPM), and Light-Dark Transition tests. Neuronal cytoarchitecture was analyzed in the ventral hippocampal CA1, basolateral amygdala (BLA), and medial prefrontal cortex (mPFC) using Golgi-Cox staining and Sholl analysis.
RESULTS
TD induced sex-dependent dendritic remodeling across all regions. In ventral CA1, TD males showed reduced proximal dendritic complexity, while TD females exhibited decreased dendritic branching. In the BLA, TD males displayed soma hypertrophy and a distal shift in dendritic complexity. In the mPFC, TD females showed reduced higher-order branching, while TD males exhibited increased distal complexity. Behaviorally, TD reduced anxiety-like behaviors in a test- and sex-specific manner: males showed reduced anxiety in the OFT, whereas females showed greater reductions in the EPM and increased exploration in the Light-Dark Transition test. Sociability did not show differences.
CONCLUSION
Tactile deprivation produces sex-specific cytoarchitectural reorganization in limbic circuits, which correlates with distinct alterations in anxiety-related behaviors. These findings elucidate the role of tactile experience in shaping emotional regulation in a sexually dimorphic manner.
Christian Peregrino-Ramírez, Nereida Ibarra-Castañeda, David Zarate-Lopez et al.· Brain Research· 0 citations
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.
Yu-Tzu Shih, J. Alipio, Z. Klaft et al.· Nature· 2 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
Distinct neocortical regions subserve different sensory functions, yet the cellular features that distinguish neurons across cortical areas remain poorly understood. Layer (L)2/3 pyramidal neurons (PyNs) are generated at similar developmental times throughout the cortex, but whether their morphological and functional properties are shaped by areal identity programs is unclear. Here, we compared L2/3 PyNs in mouse primary somatosensory (S1) and primary visual (V1) cortices (both male and female). We observed pronounced areal differences where V1 neurons exhibited smaller and less complex dendritic arbors and displayed increased intrinsic excitability relative to their counterparts in S1. These differences were present in both juvenile and adult stages, indicating that they emerge early and persist over time. Given prior evidence implicating the transcription factor LHX2 in dendritic arborization, we tested its contribution to these differences. Loss of Lhx2 in E15.5 V1 progenitors did not alter neuronal morphology in V1, in contrast to our previous findings in S1. We found that E15.5 progenitors display lower levels of LHX2 protein in V1 than in S1; therefore, we overexpressed Lhx2 in V1 progenitors and found increased dendritic branching complexity in V1 L2/3 PyNs. Together, these findings identify LHX2 as a molecular regulator that contributes to area-specific structural differentiation of L2/3 PyNs. Our results show that PyNs arising from different regions of the dorsal pallium diverge in morphology and physiology according to the cortical area, suggesting that regionally patterned transcriptional programs help establish functional specialization across the neocortex.
