Thalamic T-Type Ca2+ Channels Mediate Frontal Lobe Dysfunctions Caused by a Hypoxia-Like Damage in the Prefrontal Cortex

Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 03/2011; 31(11):4063-73. DOI: 10.1523/JNEUROSCI.4493-10.2011
Source: PubMed


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.

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    • "The first and most frequently observed abnormal EEG pattern consists of bilaterally synchronous frontal theta waves (FTWs; Figure 1, I). Clinical EEG studies (Mayorchik, 1973; Lukashevich & Sazonova, 1996; Hughes, 1994) and neurophysiological experiments (Kim et al., 2011) showed that FTWs reflect the abnormal activity of neuronal networks in the thalamic mediodorsal nucleus (MD) and/or prefrontal cortex, together comprising the fronto-thalamic system (Goldman- Rakic & Porrino 1985; Zhang, Snyder, Shimony, Fox, & Raichle, 2010). The albeit rather indirect reasons for the thalamo-cortical origin of bilaterally synchronous FTWs are discussed in our previous paper (Kurgansky & Machinskaya, 2012). "
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    ABSTRACT: We neuropsychologically assessed cognitive deficits in 109 children with symptoms of attention-deficit/hyperactivity disorder (ADHD) and 51 children with typical development aged 7-8 and 9-10 and visually analyzed resting-state electroencephalography (EEG). The EEG recordings of children with ADHD more frequently contained EEG patterns of fronto-thalamic non-optimal functioning compared with controls, reflected by groups of bilaterally synchronous frontal theta waves (FTWs) and right hemisphere local deviations of brain electrical activity. We found cognitive impairments associated with ADHD in children with different deviations of resting-state EEG. Children with FTWs in both age groups exhibited pronounced difficulties in programming, regulation and control (executive functions), and verbal performance. Children with right hemisphere local EEG abnormalities had executive dysfunction combined with difficulties in nonverbal performance. Executive performance in typically developing children significantly improved from 7-8 to 9-10 years of age. An analysis of neuropsychological scores in children with ADHD symptoms from age 7-8 to 9-10 with the same EEG abnormalities indicated specific age-related improvement of cognitive abilities. In children whose EEG showed patterns of fronto-thalamic involvement presented significant improvement in executive and verbal performance from 7-8 to 9-10 years of age. Overcoming the same age gap in children with right hemisphere local EEG deviations significantly improved only nonverbal performance, whereas improvements in executive function were not statistically significant.
    Psychology and Neuroscience 12/2014; DOI:10.3922/j.psns.2014.4.05
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    • "These channels mediate the generation of low-threshold spikes (LTS) in response to hyperpolarizing membrane potentials elicited by inhibitory inputs. LTS regulate neural oscillations, resonance, and synchrony (Llinas and Yarom, 1986; Crunelli et al., 1989; Kim et al., 2001, 2011; Mangoni et al., 2006) (Figure 1, left). Pharmacological and genetic studies show that T-type Ca2+ channels are also involved in the generation of pathological tremors (Sinton et al., 1989; Handforth et al., 2010). "
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    ABSTRACT: Specific behavioral patterns are expressed by complex combinations of muscle coordination. Tremors are simple behavioral patterns and are the focus of studies investigating motor coordination mechanisms in the brain. T-type Ca(2+) channels mediate intrinsic neuronal oscillations and rhythmic burst spiking, and facilitate the generation of tremor rhythms in motor circuits. Despite substantial evidence that T-type Ca(2+) channels mediate pathological tremors, their roles in physiological motor coordination and behavior remain unknown. Here, we review recent progress in understanding the roles that T-type Ca(2+) channels play under pathological conditions, and discuss the potential relevance of these channels in mediating physiological motor coordination.
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    • "Motor activities were monitored at 5 min intervals in a 1 h time period by using digital video recording. Etho Vision (Noldus) was employed to analyze the video data [23]. "
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    ABSTRACT: This study reports an amelioration of abnormal motor behaviors in tetrahydrobiopterin (BH4)-deficient Spr (-/-) mice by the dietary supplementation of tyrosine. Since BH4 is an essential cofactor for the conversion of phenylalanine into tyrosine as well as the synthesis of dopamine neurotransmitter within the central nervous system, the levels of tyrosine and dopamine were severely reduced in brains of BH4-deficient Spr (-/-) mice. We found that Spr (-/-) mice display variable 'open-field' behaviors, impaired motor functions on the 'rotating rod', and dystonic 'hind-limb clasping'. In this study, we report that these aberrant motor deficits displayed by Spr (-/-) mice were ameliorated by the therapeutic tyrosine diet for 10 days. This study also suggests that dopamine deficiency in brains of Spr (-/-) mice may not be the biological feature of aberrant motor behaviors associated with BH4 deficiency. Brain levels of dopamine (DA) and its metabolites in Spr (-/-) mice were not substantially increased by the dietary tyrosine therapy. However, we found that mTORC1 activity severely suppressed in brains of Spr (-/-) mice fed a normal diet was restored 10 days after feeding the mice the tyrosine diet. The present study proposes that brain mTORC1 signaling pathway is one of the potential targets in understanding abnormal motor behaviors associated with BH4-deficiency.
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