GABAB-ergic motor cortex dysfunction in SSADH deficiency.
OBJECTIVE
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.


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.
Human Cortical Physiology and Stroke Neurorehabilitation Section, NINDS, NIH, Bethesda, MD, USA. janine.reis@uniklinik-freiburg.de
Janine
J
Reis
Leonardo G
LG
Cohen
Phillip L
PL
Pearl
Brita
B
Fritsch
Nikolai H
NH
Jung
Irene
I
Dustin
William H
WH
Theodore
D000293:Adolescent; D000328:Adult; D000592:Amino Acid Metabolism, Inborn Errors / Q000235:genetics* / Q000503:physiopathology* / Q000628:therapy; D002648:Child; D002658:Developmental Disabilities; D005260:Female; D059330:GABAergic Neurons / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009044:Motor Cortex / Q000378:metabolism / Q000503:physiopathology*; D018080:Receptors, GABA-B / Q000172:deficiency*; D050644:Succinate-Semialdehyde Dehydrogenase / Q000172:deficiency / Q000235:genetics; D050781:Transcranial Magnetic Stimulation / Q000379:methods; D055815:Young Adult
D018080:Receptors, GABA-B; D050644:Succinate-Semialdehyde Dehydrogenase