RT Journal Article
T1 GAP43 Located on Corticostriatal Terminals Restrains Novelty-Induced Hyperactivity in Mice
A1 Maroto Martínez, Irene Berenice
A1 Costas Insúa, Carlos
A1 Montero Fernández, Carlos
A1 Hermoso-López, Alba
A1 Lebouc, Margaux
A1 Bajo Grañeras, Raquel
A1 Álvaro-Blázquez, Alicia
A1 Blázquez Ortiz, Cristina
A1 Cannich, Astrid
A1 Marsicano, Giovanni
A1 Martín Herranz, Ricardo
A1 Baufreton, Jérôme
A1 Rodríguez Crespo, José Ignacio
A1 Bellocchio, Luigi
A1 Guzmán Pastor, Manuel
AB Growth-associated protein of 43 kDa (GAP43) is a key cytoskeleton-associated component of the presynaptic terminal that facilitates neuroplasticity. Downregulation of GAP43 expression has been associated to various psychiatric conditions in humans and evokes hippocampus-dependent memory impairments in mice. Despite the extensive studies conducted on hippocampal GAP43 in past decades, however, very little is known about its roles in modulating the excitatory versus inhibitory balance in other brain regions. We recently generated conditional knock-out mice in which the Gap43 gene was selectively inactivated in either telencephalic glutamatergic neurons (Gap43fl/fl;Nex1Cre mice, hereafter Glu-GAP43−/− mice) or forebrain GABAergic neurons (Gap43fl/fl;Dlx5/6Cre mice, hereafter GABA-GAP43−/− mice). Here, we show that Glu-GAP43−/− but not GABA-GAP43−/−mice of either sex show a striking hyperactive phenotype when exposed to a novel environment. This behavioral alteration of Glu-GAP43−/− mice was linked to a selective activation of dorsal-striatum neurons, as well as to an enhanced corticostriatal glutamatergic transmission and an abrogation of corticostriatal endocannabinoid-mediated long-term depression. In line with these observations, GAP43 was abundantly expressed in corticostriatal glutamatergic terminals of wild-type mice.The novelty-induced hyperactive phenotype of Glu-GAP43−/− mice was abrogated by chemogenetically inhibiting corticostriatal afferences with a Gi-coupled “designer receptor exclusively activated by designer drugs” (DREADDs), thus further supporting that novelty-induced activity is controlled by GAP43 at corticostriatal excitatory projections. Taken together, these findings show an unprecedented regulatory role of GAP43 in the corticostriatal circuitry and provide a new mouse model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity, a phenotypic shortfall that occurs in diverse psychiatric diseases.
PB Journal of Neuroscience
SN 1529-2401
YR 2024
FD 2024-07-31
LK https://hdl.handle.net/20.500.14352/114180
UL https://hdl.handle.net/20.500.14352/114180
LA eng
NO Maroto IB, Costas-Insua C, Montero-Fernández C, Hermoso-López A, Lebouc M, Bajo-Grañeras R, Álvaro-Blázquez A, Blázquez-Ortiz C, Cannich A, Marsicano M, Martín R, Baufreton J, Rodríguez-Crespo I, Bellocchio L y Guzmán M. GAP43 Located on Corticostriatal Terminals Restrains Novelty-Induced Hyperactivity in Mice. J Neurosci . 2024 Sep 25;44(39):e0701242024. doi: 10.1523/JNEUROSCI.0701-24.2024.
NO Significance StatementPsychiatric alterations such as attention deficit/hyperactivity disorder, schizophrenia, and bipolar disorder pose a significant health and socioeconomic burden to our society. Animal models that recapitulate precise phenotypic traits of those diseases are therefore warranted for developing new therapeutic interventions. Here, we found that mice lacking the protein GAP43 selectively in telencephalic glutamatergic neurons show a robust novelty-induced hyperactive phenotype, a behavioral deficit often associated to psychiatric diseases. These mice exhibit profound alterations in corticostriatal excitatory plasticity and a selective overactivation of dorsal-striatum neurons in response to a novel environment. Our findings thus unveil an important role of GAP43 in corticostriatal function and provide a new animal model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity in psychiatric disorders.
NO MICINN/FEDER
DS Docta Complutense
RD 6 abr 2025