Abstract
Glutamic acid decarboxylase of 65 kDa (GAD65) antibodies have been reported in a variety of neurological disorders such as stiff-person syndrome (SPS), sporadic ataxia and some cases of epilepsy. Since the target is believed to be the cytoplasmic enzyme GAD65, the key enzyme of γ-aminobutyric acid (GABA) synthesis, the pathophysiological role of these antibodies is poorly understood. Here, we stereotactically injected human cerebrospinal fluid (CSF) containing GAD65-antibodies into the hippocampus of rats in vivo and then prepared hippocampal slices 1–2 days after post-operative recovery. We characterized both evoked and spontaneous GABAergic transmission in vitro using sharp microelectrode and patch-clamp recordings in CA1 neurons. Intracellular recordings with sharp microelectrodes from CA1 neurons showed that evoked GABAAR- or GABABR-mediated inhibitory postsynaptic potentials (IPSP) remained unaltered in anti-GAD65 tissue. These results were confirmed with patch-clamp recordings showing no difference in evoked gabazine-sensitive inhibitory postsynaptic currents (IPSCs). In addition, spontaneous IPSCs also showed no difference between anti-GAD65 tissue and controls with respect to the mean frequency, the mean amplitude and the sIPSC distribution. In conclusion, stereotactic injection of GAD65-antibodies into the hippocampus leaves evoked and spontaneous GABAergic synaptic transmission intact. Hence, dysfunction of the inhibitory GABAergic system does not appear to be the major mechanism of epileptogenicity in this disease.
Highlights
Autoimmune encephalitis is increasingly recognized in patients with otherwise unexplained temporal lobe epilepsy
These results show that in vivo stereotactic injection of Glutamic acid decarboxylase of 65 kDa (GAD65)-antibodies into the hippocampus does not cause any depression of GABAergic synaptic transmission in vitro
Antibodies against glutamic acid decarboxylase (GAD) of 65 kDa in the cerebrospinal fluid (CSF) have been described in patients with stiff-person syndrome (SPS) (Solimena et al, 1988), and in a subgroup of patients with late-onset isolated cerebellar ataxia (Honnorat et al, 2001) or limbic encephalitis and epilepsy (Peltola et al, 2000; Saiz et al, 2008; Malter et al, 2010)
Summary
Autoimmune encephalitis is increasingly recognized in patients with otherwise unexplained temporal lobe epilepsy. GAD-antibodies were initially identified in the serum and cerebrospinal fluid (CSF) of patients with stiff-person syndrome (SPS; Solimena et al, 1988). This syndrome often occurs in association with other autoimmune diseases, mainly type 1 diabetes mellitus (DM1; Baekkeskov et al, 1990). GAD-antibodies may be found in patients with epilepsy in two different settings (Bien and Scheffer, 2011): (i) acute/subacute onset of seizures accompanied by variable degrees of cognitive and psychiatric disturbance, typically in association with MRI evidence of inflammation of mesial temporal structures (limbic encephalitis; Malter et al, 2010); and (ii) in patients with chronic epilepsy without clinical or MRI evidence of active CNS inflammation (Liimatainen et al, 2010)
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