bims-climfi Biomed News
on Cerebellar cortical circuitry
Issue of 2026–08–16
two papers selected by
Jun Maruta, Mount Sinai Health System
  1. HCAR1-mediated lactate signaling modulates motor behavior and regulates spontaneous firing in Purkinje cells.
  2. Neuromedin U receptor 2 modulates climbing fiber-Purkinje cell synaptic transmission through presynaptic protein kinase A signaling cascades in mouse cerebellar slices.
  1. iScience. 2026 Aug 21. 29(8): 116930
    HCAR1-mediated lactate signaling modulates motor behavior and regulates spontaneous firing in Purkinje cells.
    Francesca Binda, Lara Buscemi, Nicolas Gurtner, Lorenz Hirt, Jean-Yves Chatton.
      Lactate modulates several phenomena ranging from gene transcription to plasticity. Through its specific GPCR receptor HCAR1, lactate acts as a signaling molecule modulating neuronal excitability. Silencing lactate signaling promotes anxiety-like behavior and worsens epileptic seizures, highlighting the central role of HCAR1 in brain function. HCAR1 expression in the cerebellum supports the role of the receptor in motor coordination. Early experimental evidence suggesting HCAR1 expression in cerebellar Purkinje cells (PCs) together with its ability to modulate neuronal excitability qualifies the receptor as a possible modulator of PC activity with important implications for cerebellar-mediated diseases. This hypothesis was investigated using behavioral analysis and ex vivo electrophysiology that showed gait instability and motor learning defects in HCAR1 knockout mice associated with increased PC firing. We identified HCN channels as the downstream target of HCAR1. We conclude that lactate signaling is a modulator of PC excitability and revealed the HCAR1 role in motor behavior.
    Keywords:  HCAR1; HCN; Purkinje cells; cerebellum; glia; hydroxycarboxylic acid receptor 1; lactate; motor learning; spontaneous firing
    DOI:  https://doi.org/10.1016/j.isci.2026.116930
  2. Neuroreport. 2026 Jul 31.
    Neuromedin U receptor 2 modulates climbing fiber-Purkinje cell synaptic transmission through presynaptic protein kinase A signaling cascades in mouse cerebellar slices.
    Mei-Rui Li, Ri-Long Piao, Xu-Dong Zhang, Wen-Cai Weng, Chun-Ping Chu, De-Lai Qiu.
       OBJECTIVE: The central neuromedin U receptor 2 (NMUR2) participates in regulating neuronal activity and synaptic transmission. This study aimed to explore the functional role of NMUR2 in climbing fiber-Purkinje cell synaptic transmission in mouse cerebellar slices.
    METHODS: Climbing fiber-Purkinje cell excitatory postsynaptic currents (EPSCs) and miniature excitatory postsynaptic currents (mEPSCs) were recorded from Purkinje cells using an Axopatch 700B patch-clamp amplifier. Western blot, glutamate sensor fluorescence imaging, and immunohistochemistry were applied to measure phosphorylated protein kinase A (PKA) levels, climbing fiber terminal glutamate release, and NMUR2 expression, respectively.
    RESULTS: Bath application of the selective NMUR2 agonist CPN-219 reduced the amplitude and area under the curve of climbing fiber-Purkinje cell EPSCs and increased the paired-pulse ratio (N2/N1). The CPN-219-induced suppression of EPSCs was reversed by an adenylyl cyclase activator and occluded by an AC inhibitor. The CPN-219-mediated inhibitory effect on EPSCs was completely abolished by bath perfusion of the PKA inhibitor, but not by intracellular PKA inhibition. Western blot analysis revealed that CPN-219 decreased phosphorylated PKA levels in cerebellar molecular layer tissue. Furthermore, CPN-219 markedly attenuated Ca2+ transients and complex spike activity in Purkinje cells, suppressed climbing fiber-evoked glutamate fluorescent signals, and decreased mEPSC frequency, with no significant alteration in mEPSC amplitude. Moreover, immunohistochemical staining showed NMUR2 immunoreactivity distributed throughout the somata and dendritic arbors of Purkinje cells.
    CONCLUSION: These results indicate that NMUR2 activation suppresses climbing fiber-Purkinje cell synaptic transmission in mouse cerebellar slices predominantly via a mechanism consistent with a presynaptic adenylyl cyclase-PKA signaling cascade.
    Keywords:  calcium imaging; cerebellar cortex; climbing fiber–Purkinje cell synaptic transmission; glutamate sensor; immunohistochemistry; miniature excitatory postsynaptic currents; neuromedin U receptor 2
    DOI:  https://doi.org/10.1097/WNR.0000000000002298
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