Ccp1 depletion disrupts network integration of hippocampal parvalbumin interneurons

Romain Le Bail; Bernard Lakaye; Ira Espuny-Camacho; Carsten Janke; Maria M Magiera; Dominique Engel; Carla G Silva; Laurent Nguyen

doi:10.1016/j.isci.2025.113215

Ccp1 depletion disrupts network integration of hippocampal parvalbumin interneurons

iScience. 2025 Jul 30;28(9):113215. doi: 10.1016/j.isci.2025.113215. eCollection 2025 Sep 19.

Authors

Romain Le Bail¹, Bernard Lakaye¹, Ira Espuny-Camacho¹, Carsten Janke^{2

3}, Maria M Magiera^{2

3}, Dominique Engel¹, Carla G Silva¹, Laurent Nguyen^{1

4}

Affiliations

¹ Laboratory of Molecular Regulation of Neurogenesis, GIGA Institute, University of Liège, CHU Sart Tilman, 4000 Liège, Belgium.
² Institut Curie, Université PSL, CNRS UMR3348, Orsay, France.
³ Université Paris-Saclay, CNRS UMR3348, Orsay, France.
⁴ WELBIO Department, WEL Research Institute, Avenue Pasteur, 6, 1300 Wavre, Belgium.

Abstract

Post-translational modifications (PTMs) of microtubules (MTs) endow them with specific properties that are essential for key cellular functions, such as axonal transport. Polyglutamylation, a PTM that accumulates in long-lived MTs, has been linked to neurodegeneration in the cerebellum when in excess. While hyperglutamylation of MTs leads to neurodegeneration and disrupts the function of specific neuronal subtypes like Purkinje cells, cortical neurons, and hippocampal excitatory neurons, little is known about its impact on inhibitory interneurons and their functional integration into local networks. In this study, we generated a conditional knockout mouse model to deplete cytosolic carboxypeptidase 1 (Ccp1) in GABAergic neurons, a key MT deglutamylase expressed by hippocampal interneurons. Our findings reveal that the loss of Ccp1 has a profound effect on hippocampal parvalbumin (PV)-expressing interneurons, impairing their MT-dependent transport and reducing their perisomatic inhibition of pyramidal cells (PCs) in the CA2 region of the hippocampus.

Keywords: Cell biology; Genetics; Molecular biology; Neuroscience; Physiology.