Biology subjects

Monday, H. R.

Publications and source records attributed to Monday, H. R..

5 recordsLinked to original sources

bioRxiv2025

Degraded sensory coding in a mouse model of Scn2a-related disorder and its rescue by CRISPRa gene activation

Heterozygous loss-of-function mutations in SCN2A, a sodium channel gene expressed in cortical pyramidal (PYR) cells, lead to a neurodevelopmental disorder characterized by autism, intellectual disability, and cortical sensory dysfunction. In Scn2a+/- mice, PYR dendritic excitability and synapses are impaired, but cortical information processing deficits are unknown. In the whisker somatosensory cortex, we found strongly degraded somatotopic tuning of PYR cells, profoundly blurred whisker maps, and impaired population coding, despite normal overall firing rates. This constitutes a robust biomarker for Scn2a-related cortical dysfunction. Parvalbumin (PV) interneurons were also unexpectedly hypofunctional. We tested for rescue of coding deficits in post-critical period, young adult mice by viral delivery of CRISPR activation (CRISPRa) reagents that upregulate Scn2a. CRISPRa treatment normalized cortical sensory representations at the single-unit and map levels. This suggests that therapy to increase Scn2a expression may be effective in normalizing cortical function in Scn2a loss-of-function disorder, even in older children or adults.

neuroscience↗

bioRxiv2025

Physiological and molecular impairment of PV circuit homeostasis in mouse models of autism

Circuit dysfunction in autism may involve a failure of homeostatic plasticity. To test this, we studied parvalbumin (PV) interneurons which exhibit rapid homeostatic plasticity of intrinsic excitability following whisker deprivation in mouse somatosensory cortex. Brief deprivation reduces PV excitability by increasing Kv1 current to increase PV spike threshold. We found that PV homeostatic plasticity is disrupted in Tsc2+/-and Fmr1-/- models of autism. In wildtype mice, deprivation elevates the transcription factor ER81 which drives Kcna1 transcription, increasing Kv1.1 protein in the axon initial segment and soma. These molecular signatures of homeostasis were absent in Tsc2+/- and Fmr1-/-. Whisker enrichment increased PV excitability, but not in Tsc2+/-, indicating that homeostasis is lost bidirectionally. Deprivation reduced feedforward L4-L2/3 inhibition in wildtype but not Tsc2+/-mice. Thus, two autism models show a convergent loss of PV circuit homeostasis at physiological and molecular levels, potentially contributing to sensory processing impairments.

neuroscience↗

bioRxiv2024

Molecular states underlying neuronal cell type development and plasticity in the whisker cortex

Mouse whisker somatosensory cortex (wS1) is a major model system to study the experience-dependent plasticity of cortical neuron physiology, morphology, and sensory coding. However, the role of sensory experience in regulating neuronal cell type development and gene expression in wS1 remains poorly understood. We assembled and annotated a transcriptomic atlas of wS1 during postnatal development comprising 45 molecularly distinct neuronal types that can be grouped into eight excitatory and four inhibitory neuron subclasses. Using this atlas, we examined the influence of whisker experience from postnatal day (P) 12, the onset of active whisking, to P22, on the maturation of molecularly distinct cell types. During this developmental period, when whisker experience was normal, [~]250 genes were regulated in a neuronal subclass-specific fashion. At the resolution of neuronal types, we found that only the composition of layer (L) 2/3 glutamatergic neuronal types, but not other neuronal types, changed substantially between P12 and P22. These compositional changes resemble those observed previously in the primary visual cortex (V1), and the temporal gene expression changes were also highly conserved between the two regions. In contrast to V1, however, cell type maturation in wS1 is not substantially dependent on sensory experience, as 10-day full-face whisker deprivation did not influence the transcriptomic identity and composition of L2/3 neuronal types. A one-day competitive whisker deprivation protocol also did not affect cell type identity but induced moderate changes in plasticity-related gene expression. Thus, developmental maturation of cell types is similar in V1 and wS1, but sensory deprivation minimally affects cell type development in wS1. Highlights- A single-nucleus transcriptomic atlas of the whisker somatosensory cortex (wS1) during early postnatal development - Different neuronal subclasses in wS1 show distinct developmental gene expression changes - The composition of L2/3 glutamatergic neurons changes between the second and the third postnatal week - Developmental gene expression and cell type changes are conserved between wS1 and the primary visual cortex (V1) - Unlike V1, these changes are not affected by prolonged sensory deprivation - Brief whisker deprivation induces subclass-specific activity-dependent gene expression in a whisker column-specific fashion

neuroscience↗

bioRxiv2021

Presynaptic FMRP and local protein synthesis support structural and functional plasticity of glutamatergic axon terminals

Learning and memory critically rely on long-lasting, synapse-specific modifications. While postsynaptic forms of plasticity typically require local protein synthesis, whether and how local protein synthesis contributes to presynaptic changes remains unclear. Here, we examined the hippocampal mossy fiber (MF)-CA3 synapse which expresses both structural and functional presynaptic plasticity. We report that MF boutons synthesize protein locally and contain ribosomes. Long-term potentiation of MF-CA3 synaptic transmission (MF-LTP) was associated with translation-dependent enlargement of MF boutons. Moreover, increasing in vitro and in vivo MF activity enhanced protein synthesis in MFs. Remarkably, deletion of presynaptic Fragile X mental retardation protein (FMRP), an RNA-binding protein expressed in MF boutons and previously implicated in local postsynaptic protein synthesis-dependent plasticity, blocked structural and functional MF-LTP, suggesting that FMRP is a critical regulator of presynaptic function. Thus, presynaptic FMRP and protein synthesis dynamically control presynaptic structure and function in the mature brain. HighlightsO_LIMossy fiber boutons (MFBs) synthesize protein locally and contain ribosomes C_LIO_LILocal presynaptic translation is increased by in vitro and in vivo GC activity C_LIO_LIMFB structural plasticity relies on de novo protein synthesis. C_LIO_LIPresynaptic FMRP is required for MF-CA3 structural and functional plasticity C_LI In BriefMonday et al. report that FMRP and protein synthesis in hippocampal mossy fiber boutons mediate functional and structural presynaptic plasticity.

neuroscience↗

bioRxiv2020

CB1 receptor-mediated inhibitory LTD triggers presynaptic remodeling via protein synthesis and ubiquitination

Long-lasting forms of postsynaptic plasticity commonly involve protein synthesis-dependent structural changes of dendritic spines. However, the relationship between protein synthesis and presynaptic structural plasticity remains unclear. Here, we investigated structural changes in cannabinoid-receptor 1 (CB1)-mediated long-term depression of inhibitory transmission (iLTD), a form of presynaptic plasticity that requires protein synthesis and involves a long-lasting reduction in GABA release. We found that CB1-iLTD in acute rat hippocampal slices was associated with protein synthesis-dependent presynaptic structural changes. Using proteomics, we determined that CB1 activation in hippocampal neurons resulted in increased ribosomal proteins and initiation factors, but decreased levels of proteins involved in regulation of the actin cytoskeleton, such as Arp2/3, and presynaptic release. Moreover, while CB1-iLTD increased ubiquitin/proteasome activity, ubiquitination but not proteasomal degradation was critical for structural and functional presynaptic CB1-iLTD. Thus, CB1-iLTD relies on both protein synthesis and ubiquitination to elicit structural changes that underlie long-term reduction of GABA release.

neuroscience↗