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GAP43 Located on Corticostriatal Terminals Restrains Novelty-Induced Hyperactivity in Mice
Irene B Maroto1,2,3, Carlos Costas-Insua1,2,3, Carlos Montero-Fernández1,2,3
1Department of Biochemistry and Molecular Biology, Schools of Biology and Chemistry, Instituto Universitario de Investigación Neuroquímica (IUIN), Complutense University, Madrid ES-28040, Spain.
Summary
Growth-associated protein 43 (GAP43) in excitatory neurons drives novelty-induced hyperactivity by regulating corticostriatal circuits. This study reveals GAP43
Area of Science:
- Neuroscience
- Molecular Biology
- Behavioral Genetics
Background:
- Growth-associated protein 43 (GAP43) is crucial for neuroplasticity at presynaptic terminals.
- GAP43 dysfunction is linked to psychiatric disorders and memory deficits.
- Its role in balancing excitation/inhibition in brain regions beyond the hippocampus is largely unknown.
Purpose of the Study:
- To investigate the role of GAP43 in telencephalic glutamatergic and forebrain GABAergic neurons.
- To elucidate GAP43's function in modulating excitatory-inhibitory balance and behavior.
- To establish a novel mouse model for studying hyperactivity in psychiatric diseases.
Main Methods:
- Generated conditional knock-out mice: Glu-GAP43-/- (telencephalic glutamatergic neurons) and GABA-GAP43-/- (forebrain GABAergic neurons).
- Assessed behavioral phenotypes, focusing on novelty-induced hyperactivity.
- Utilized chemogenetics with DREADDs to inhibit corticostriatal pathways.
Main Results:
- Glu-GAP43-/- mice exhibited significant novelty-induced hyperactivity; GABA-GAP43-/- mice did not.
- Hyperactivity in Glu-GAP43-/- mice correlated with dorsal-striatum activation and enhanced corticostriatal glutamatergic transmission.
- Endocannabinoid-mediated long-term depression at corticostriatal synapses was abrogated in Glu-GAP43-/- mice.
- Chemogenetic inhibition of corticostriatal afferences normalized hyperactivity in Glu-GAP43-/- mice.
Conclusions:
- GAP43 plays a critical regulatory role in corticostriatal circuitry.
- Selective deletion of GAP43 in glutamatergic neurons disrupts excitatory transmission and causes hyperactivity.
- These findings highlight GAP43's involvement in novelty processing and provide a model for psychiatric conditions characterized by hyperactivity.
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