Long-term depression–inductive stimulation causes long-term potentiation in mouse Purkinje cells with a mutant thyroid hormone receptor

Abstract

Thyroid hormones (THs) regulate gene expression by binding to nuclear TH receptors (TRs) in the cell. THs are indispensable for brain development. However, we have little knowledge about how congenital hypothyroidism in neurons affects functions of the central nervous system in adulthood. Here, we report specific TH effects on functional development of the cerebellum by using transgenic mice overexpressing a dominant-negative TR (Mf-1) specifically in cerebellar Purkinje cells (PCs). Adult Mf-1 mice displayed impairments in motor coordination and motor learning. Surprisingly, long-term depression (LTD)–inductive stimulation caused long-term potentiation (LTP) at parallel fiber (PF)–PC synapses in adult Mf-1 mice, although there was no abnormality in morphology or basal properties of PF–PC synapses. The LTP phenotype was turned to LTD in Mf-1 mice when the inductive stimulation was applied in an extracellular high-Ca 2+ condition. Confocal calcium imaging revealed that dendritic Ca 2+ elevation evoked by LTD-inductive stimulation is significantly reduced in Mf-1 PCs but not by PC depolarization only. Single PC messenger RNA quantitative analysis showed reduced expression of SERCA2 and IP 3 receptor type 1 in Mf-1 PCs, which are essential for mGluR1-mediated internal calcium release from endoplasmic reticulum in cerebellar PCs. These abnormal changes were not observed in adult-onset PC-specific TH deficiency mice created by adeno-associated virus vectors. Thus, we propose the importance of TH action during neural development in establishing proper cerebellar function in adulthood, independent of its morphology. The present study gives insight into the cellular and molecular mechanisms underlying congenital hypothyroidism–induced dysfunctions of central nervous system and cerebellum.

Glial modulation of the parallel memory formation

“…In our current study, we show that ArchT photoactivation can completely prevent LTD induction. We also show It has been established that reduced Ca 2+ increase in PCs can produce LTP instead of LTD at the PF-PC synapse (Boyden et al, 2004;Jörntell & Hansel, 2006;Ninomiya et al, 2022). It is note- et al, 2014).…”

“…It has been established that reduced Ca 2+ increase in PCs can produce LTP instead of LTD at the PF‐PC synapse (Boyden et al, 2004; Jörntell & Hansel, 2006; Ninomiya et al, 2022). It is noteworthy that astrocyte‐specific LRRC8A‐cKO or ArchT photoactivation during HOKR training not only prevented HOKR performance increase during online training but also resulted in a decrease in the online gain (Figures 3–5).…”

Ghrelin signaling in the cerebellar cortex enhances GABAergic transmission onto Purkinje cells

“…On the other hand, GHS-R1a activation also activates βγ subunits of G o -proteins, resulting in PKA-mediated suppression of Ca v 2.1 voltage-gated Ca 2+ channels 16 . This signaling pathway possibly reduces intracellular Ca 2+ and contributes to the induction of LTP 42 , 43 . Additionally, a previous study reported that inhibition from MLIs promotes LTP at PF-PC synapses 44 ; thus, the ghrelin-mediated facilitation of sIPSCs could contribute to LTP-induction.…”