title: Thalamic T-type Ca²+ channels mediate frontal lobe dysfunctions caused by a hypoxia-like damage in the prefrontal cortex.
abstract: Hypoxic damage to the prefrontal cortex (PFC) has been implicated in the frontal lobe dysfunction found in various neuropsychiatric disorders. The underlying subcortical mechanisms, however, have not been well explored. In this study, we induced a PFC-specific hypoxia-like damage by cobalt-wire implantation to demonstrate that the role of the mediodorsal thalamus (MD) is critical for the development of frontal lobe dysfunction, including frontal lobe-specific seizures and abnormal hyperactivity. Before the onset of these abnormalities, the cross talk between the MD and PFC nuclei at theta frequencies was enhanced. During the theta frequency interactions, burst spikes, known to depend on T-type Ca(2+) channels, were increased in MD neurons. In vivo knockout or knockdown of the T-type Ca(2+) channel gene (Ca(V)3.1) in the MD substantially reduced the theta frequency MD-PFC cross talk, frontal lobe-specific seizures, and locomotor hyperactivity in this model. These results suggest a two-step model of prefrontal dysfunction in which the response to a hypoxic lesion in the PFC results in abnormal thalamocortical feedback driven by thalamic T-type Ca(2+) channels, which, in turn, leads to the onset of neurological and behavioral abnormalities. This study provides valuable insights into preventing the development of neuropsychiatric disorders arising from irreversible PFC damage.
authors.affiliation: Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
authors.forename: Jeongjin
authors.initials: J
authors.lastname: Kim
authors.forename: Jeonghoon
authors.initials: J
authors.lastname: Woo
authors.forename: Young-Gyun
authors.initials: YG
authors.lastname: Park
authors.forename: Sujin
authors.initials: S
authors.lastname: Chae
authors.forename: Seonmi
authors.initials: S
authors.lastname: Jo
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Choi
authors.forename: Hong Young
authors.initials: HY
authors.lastname: Jun
authors.forename: Young Il
authors.initials: YI
authors.lastname: Yeom
authors.forename: Seong Hoon
authors.initials: SH
authors.lastname: Park
authors.forename: Kyung Hwan
authors.initials: KH
authors.lastname: Kim
authors.forename: Hee-Sup
authors.initials: HS
authors.lastname: Shin
authors.forename: Daesoo
authors.initials: D
authors.lastname: Kim
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D020747:Calcium Channels, T-Type / Q000378:metabolism*; D003214:Conditioning, Classical / Q000502:physiology; D004594:Electrophysiology; D005239:Fear; D005260:Female; D005547:Foreign Bodies; D005625:Frontal Lobe / Q000293:injuries* / Q000378:metabolism / Q000503:physiopathology*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D013788:Thalamus / Q000378:metabolism*
chemical_list: D020747:Calcium Channels, T-Type