Differentially Altered NMDAR Dependent and Independent Long-Term Potentiation in the CA3 Subfield in a Model of Anti-NMDAR Encephalitis

• Published in: Frontiers in synaptic neuroscience 2018-07, Vol.10, p.26-26
• Main Authors: Blome, Roman, Bach, Willi, Guli, Xiati, Porath, Katrin, Sellmann, Tina, Bien, Christian G, Köhling, Rüdiger, Kirschstein, Timo
• Format: Article
• Language: English
• Subjects: associational-commissural fibers; epileptiform afterpotentials; LTP; mossy fibers; Neuroscience; NMDA receptor
• ISSN: 1663-3563; 1663-3563
• DOI: 10.3389/fnsyn.2018.00026

: Autoantibodies against NMDA receptors (NMDAR) in the cerebrospinal fluid (CSF) from anti-NMDAR encephalitis patients have been suggested to be pathogenic since in previous studies using patient CSF, NMDAR-dependent processes such as long-term potentiation (LTP) were compromised. However, autoantibodies may represent a family of antibodies targeted against different epitopes, and CSF may contain further autoantibodies. Here, we tested the specificity of the autoantibody by comparing NMDAR-dependent and NMDAR-independent LTP within the same hippocampal subfield, CA3, using CSF samples from four anti-NMDAR encephalitis patients and three control patients. : We performed a stereotactic injection of patient-derived cell-free CSF with proven presence or absence of NMDAR-antibodies into the rat hippocampus . Hippocampal brain slices were prepared 1-8 days after intrahippocampal injection, and NMDAR-dependent LTP at the associational-commissural (A/C) fiber-CA3 synapse was compared to NMDAR-independent LTP at the mossy fiber (MF)-CA3 synapse. : The LTP magnitude at A/C fiber-CA3 synapses in slices from control-CSF-treated animals (168 ± 8% = 54) was significantly higher than LTP in slices from NMDAR-CSF-treated animals (139 ± 9%, = 40; = 0.015), although there was some variation between the individual CSF samples. We found residual LTP in NMDAR-CSF-treated tissue which could be abolished by the NMDAR inhibitor D-AP5. Moreover, the CA3 field excitatory postsynaptic potential (fEPSP) was followed by epileptiform afterpotentials in 5% of slices (4/78) from control-CSF-treated animals, but in 26% of slices (12/46) from NMDAR-CSF-treated animals ( = 0.002). Application of the LTP-inducing paradigm increased the proportion of slices with epileptiform afterpotentials, but D-AP5 significantly reduced the occurrence of epileptiform afterpotentials only in NMDAR-CSF-treated, but not in control tissue. At the MF synapse, no significant difference in LTP values of control-CSF and in NMDAR-CSF-treated tissue was observed indicating that NMDAR-independent MF-LTP is intact in NMDAR-CSF-treated tissue. : These findings indicate that anti-NMDAR containing CSF impairs LTP at the A/C fiber-CA3 synapse, although there is substantial variation among CSF samples suggesting different epitopes among patient-derived antibodies. The differential inhibition of LTP at this synapse in contrast to the MF-CA3 synapse suggests the specificity and underlines the pathophysiological role of the N