title: Loss of cyclin-dependent kinase 5 from parvalbumin interneurons leads to hyperinhibition, decreased anxiety, and memory impairment.
abstract: Perturbations in fast-spiking parvalbumin (PV) interneurons are hypothesized to be a major component of various neuropsychiatric disorders; however, the mechanisms regulating PV interneurons remain mostly unknown. Recently, cyclin-dependent kinase 5 (Cdk5) has been shown to function as a major regulator of synaptic plasticity. Here, we demonstrate that genetic ablation of Cdk5 in PV interneurons in mouse brain leads to an increase in GABAergic neurotransmission and impaired synaptic plasticity. PVCre;fCdk5 mice display a range of behavioral abnormalities, including decreased anxiety and memory impairment. Our results reveal a central role of Cdk5 expressed in PV interneurons in gating inhibitory neurotransmission and underscore the importance of such regulation during behavioral tasks. Our findings suggest that Cdk5 can be considered a promising therapeutic target in a variety of conditions attributed to inhibitory interneuronal dysfunction, such as epilepsy, anxiety disorders, and schizophrenia.
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Andrii
authors: A
authors: Rudenko
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Jinsoo
authors: J
authors: Seo
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Ji
authors: J
authors: Hu
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Susan C
authors: SC
authors: Su
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Froylan Calderon
authors: FC
authors: de Anda
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Omer
authors: O
authors: Durak
authors: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115.
authors: Maria
authors: M
authors: Ericsson
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139.
authors: Marie
authors: M
authors: Carlén
authors: Picower Institute for Learning and Memory, Department of Brain and Cognitive Sciences, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, Broad Institute, Cambridge, Massachusetts 02142, and lhtsai@mit.edu.
authors: Li-Huei
authors: LH
authors: Tsai
mesh_terms: D000818:Animals; D001007:Anxiety / Q000235:genetics / Q000523:psychology*; D001522:Behavior, Animal / Q000502:physiology; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D007266:Inhibition, Psychological; D007395:Interneurons / Q000201:enzymology / Q000378:metabolism*; D018782:Maze Learning / Q000502:physiology; D008569:Memory Disorders / Q000235:genetics / Q000523:psychology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000235:genetics / Q000502:physiology; D010320:Parvalbumins / Q000378:metabolism*; D009435:Synaptic Transmission / Q000235:genetics / Q000502:physiology; D013572:Synaptic Vesicles / Q000648:ultrastructure; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D010320:Parvalbumins; D005680:gamma-Aminobutyric Acid; D051360:Cyclin-Dependent Kinase 5
keywords: anxiety; axon initial segment; cognition; cyclin-dependent kinase 5; fast-spiking (FS) parvalbumin (PV)-interneurons