bims-climfi Biomed News
on Cerebellar cortical circuitry
Issue of 2026–08–02
two papers selected by
Jun Maruta, Mount Sinai Health System
  1. Defining a subclass of cerebellar molecular layer interneurons by their Purkinje cell feedback.
  2. Chemogenetic Activation of LC Noradrenergic Afferents Facilitates Cerebellar CF-PC LTD via Presynaptic α2A-AR/CDK5/PKA Signaling.
  1. Cell Rep. 2026 Jul 31. pii: S2211-1247(26)00788-6. [Epub ahead of print]45(8): 117710
    Defining a subclass of cerebellar molecular layer interneurons by their Purkinje cell feedback.
    Jinsook Kim, George J Augustine.
      A subset of molecular layer interneurons (MLIs), previously termed Purkinje cell-input MLIs (PC-MLIs), receive inhibitory feedback from Purkinje cells (PCs), the sole output neurons of the cerebellar cortex. Here we have characterized the properties of these cells. Compared to other MLIs and Purkinje layer interneurons, they have distinct axonal and dendritic morphology, intrinsic electrical properties, and expression of marker genes. These interneurons also display distinctive circuit connectivity: they are the only MLI that receives feedback inhibition from PCs and receive minimal inhibition from basket or stellate cells. In turn, they mainly inhibit PCs and basket cells. These interneurons do not form electrical synapses with other neurons but receive the same excitatory inputs-from parallel fibers and climbing fibers -as other MLIs. These properties allow them to shape the output of the cerebellar cortex differently from other interneurons and may account for their proposed role in cerebellar motor learning.
    Keywords:  CP: cell biology; CP: neuroscience; Purkinje cell; cell classification; cerebellum; feedback inhibition; gene expression; intrinsic electrical properties; molecular layer interneurons
    DOI:  https://doi.org/10.1016/j.celrep.2026.117710
  2. Biomolecules. 2026 Jul 17. pii: 1042. [Epub ahead of print]16(7):
    Chemogenetic Activation of LC Noradrenergic Afferents Facilitates Cerebellar CF-PC LTD via Presynaptic α2A-AR/CDK5/PKA Signaling.
    Xu-Dong Zhang, Ying-Han Xu, Wang-Tong Wu, Lang-Yue Zheng, Xin-Yi Xu, Chun-Ping Chu, De-Lai Qiu.
      Cerebellar climbing fiber-Purkinje cell (CF-PC) long-term depression (LTD) plays a critical role in motor learning and is modulated by locus coeruleus (LC) noradrenergic afferents via distinct adrenergic receptor (AR) subtypes. Nevertheless, the mechanisms underlying LC noradrenergic neuron-mediated regulation of CF-PC LTD remain poorly understood. Here, we investigated the effects of chemogenetic activation of LC noradrenergic afferents on CF-PC LTD in cerebellar slices from dopamine β-hydroxylase (DBH)-Cre mice using electrophysiology, glutamate sensor imaging, immunofluorescence and pharmacological approaches. Tetanic stimulation (5 Hz) of CFs induced CF-PC LTD under control conditions, and this LTD was enhanced by chemogenetic activation of LC noradrenergic afferents. Blockade of group I metabotropic glutamate receptors (mGluR1) abolished LTD under control conditions, whereas chemogenetic activation of LC noradrenergic afferents triggered a novel form of CF-PC LTD accompanied by an increased N2/N1 ratio. With mGluR1 blocked, chemogenetic activation of LC noradrenergic afferents failed to trigger the novel CF-PC LTD following blockade of α2-AR or α2A-AR, but not α2B-AR or α2C-AR. Importantly, chemogenetic activation of LC noradrenergic afferents triggered LTD of glutamate fluorescence at CF terminals, which was abolished by blockade of α2-AR or α2A-AR, but not α2B-AR or α2C-AR. Notably, inhibition of either cyclin-dependent kinase 5 (CDK5) or presynaptic, but not postsynaptic, protein kinase A (PKA) completely abolished the CF-PC LTD triggered by chemogenetic activation of LC noradrenergic afferents in mouse cerebellar slices. Immunofluorescence results showed robust α2A-AR expression throughout the cerebellar molecular layer, with intense signals along PC dendrites and clear colocalization with vesicular glutamate transporter 2 (vGluT2) at cerebellar CF terminals. These results indicate that activation of LC noradrenergic afferents potentiates CF-PC LTD by triggering Glu-LTD at CF terminals through the α2A-AR/CDK5/PKA signaling cascade in the mouse cerebellar cortex.
    Keywords:  cerebellum; chemogenetic activation; climbing fiber–Purkinje cell synaptic plasticity; cyclin–dependent kinase 5 (CDK5); locus coeruleus; protein kinase A (PKA); α2-adrenergic receptor
    DOI:  https://doi.org/10.3390/biom16071042
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