Dataset Information

GABAB-ergic motor cortex dysfunction in SSADH deficiency.

ABSTRACT:

Objective

Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and ?-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.

Methods

We quantified the magnitude of excitation and inhibition in primary motor cortex (M1) in patients with SSADH deficiency, their parents (obligate heterozygotes), age-matched healthy young controls, and healthy adults using single and paired pulse transcranial magnetic stimulation (TMS).

Results

Long interval intracortical inhibition was significantly reduced and the cortical silent period was significantly shortened in patients with SSADH deficiency compared to heterozygous parents and control groups.

Conclusions

Since long interval intracortical inhibition and cortical silent period are thought to reflect GABA(B) receptor-mediated inhibitory circuits, our results point to a particularly GABA(B)-ergic motor cortex dysfunction in patients with SSADH deficiency. This human phenotype is consistent with the proposed mechanism of use-dependent downregulation of postsynaptic GABA(B) receptors in SSADH deficiency animal models. Additionally, the results suggest autoinhibition of GABAergic neurons. This first demonstration of altered GABA(B)-ergic function in patients with SSADH deficiency may help to explain clinical features of the disease, and suggest pathophysiologic mechanisms in other neurotransmitter-related disorders.

SUBMITTER: Reis J

PROVIDER: S-EPMC3385496 | biostudies-literature | 2012 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

GABAB-ergic motor cortex dysfunction in SSADH deficiency.

Reis Janine J Cohen Leonardo G LG Pearl Phillip L PL Fritsch Brita B Jung Nikolai H NH Dustin Irene I Theodore William H WH

Neurology 20120620 1

<h4>Objective</h4>Succinic semialdehyde dehydrogenase (SSADH) deficiency is a rare autosomal recessive disorder of GABA degradation leading to elevations in brain GABA and γ-hydroxybutyric acid (GHB). The effect of chronically elevated GABA and GHB on cortical excitability is unknown. We hypothesized that use-dependent downregulation of GABA receptor expression would promote cortical disinhibition rather than inhibition, predominantly via presynaptic GABAergic mechanisms.<h4>Methods</h4>We quant ...[more]

PMID: 22722631

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Project description:Studying changes in cortical oscillations can help elucidate the mechanistic link between receptor physiology and the clinical effects of anaesthetic drugs. Propofol, a GABA-ergic drug produces divergent effects on visual cortical activity: increasing induced gamma-band responses (GBR) while decreasing evoked responses. Dexmedetomidine, an α2- adrenergic agonist, differs from GABA-ergic sedatives both mechanistically and clinically as it allows easy arousability from deep sedation with less cognitive side-effects. Here we use magnetoencephalography (MEG) to characterize and compare the effects of GABA-ergic (propofol) and non-GABA-ergic (dexmedetomidine) sedation, on visual and motor cortical oscillations. Sixteen male participants received target-controlled infusions of propofol and dexmedetomidine, producing mild-sedation, in a placebo-controlled, cross-over study. MEG data was collected during a combined visuomotor task. The key findings were that propofol significantly enhanced visual stimulus induced GBR (44% increase in amplitude) while dexmedetomidine decreased it (40%). Propofol also decreased the amplitudes of the Mv100 (visual M100) (27%) and Mv150 (52%) visual evoked fields (VEF), whilst dexmedetomidine had no effect on these. During the motor task, neither drug had any significant effect on movement related gamma synchrony (MRGS), movement related beta de-synchronisation (MRBD) or Mm100 (movement-related M100) movement-related evoked fields (MEF), although dexmedetomidine slowed the Mm300. Dexmedetomidine increased (92%) post-movement beta synchronisation/rebound (PMBR) power while propofol reduced it (70%, statistically non- significant). Overall, dexmedetomidine and propofol, at equi-sedative doses, produce contrasting effects on visual induced GBR, VEF, PMBR and MEF. These findings provide a mechanistic link between the known receptor physiology of these sedative drugs with their known clinical effects and may be used to explore mechanisms of other anaesthetic drugs on human consciousness.

Dataset Information

GABAB-ergic motor cortex dysfunction in SSADH deficiency.

Objective

Methods

Results

Conclusions

Publications

GABAB-ergic motor cortex dysfunction in SSADH deficiency.

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