Spatial learning in the network of hippocampal place cells: Altering memory using a mouse model of passive transfer of antibodies from patients with anti-NMDAR encephalitis

Abstract

[eng] Anti-NMDAR encephalitis is the most frequent antibody-mediated encephalitis known to date, in which patients develop specific antibodies directed against the N-methyl-D-aspartate receptors (NMDARs) in the central nervous system. These antibodies disrupt the function of NMDARs resulting in various psychiatric and neurological symptoms. These antibodies, on the one hand, reduce the density of synaptic NMDARs in brain tissues, particularly in the hippocampus; and on the other hand, cause impairment of cognitive functions, including severe memory problems. The missing link about the memory deficits in anti-NMDAR encephalitis is how the antibody-mediated synaptic changes translate to changes in the neural activity of cells involved in encoding memories, which leads to cognitive and behavioral declines. To fill this knowledge gap, this thesis investigated the dynamics of neuronal activity of hippocampal cells, under the effect of NMDAR antibodies, in an animal model that was developed previously by passive transfer of CSF from patients with anti-NMDAR encephalitis to mice cerebroventricular system. The animal model was combined with repeated calcium imaging of the same population of hippocampal CA1 neurons over three months, along with two behavioral tasks for assessing both retrograde and anterograde memory loss. This thesis mainly investigates the role of hippocampal place-cells in encoding and storing spatial information and memory. Place-cells are chosen because of their hypothesized role as the neural substrate of memory. Place-cells develop spatially-tuned neural activities (place-fields) for encoding preferred spatial locations and retain their neuronal codes over periods of months. At the neural activity level, therefore, re-activation of the same place-fields when the animal visits the same spatial location is a readout of the animals’ memory. It is also known that consolidation of these spatial memories upon stabilization of the place-fields is highly dependent on NMDAR. In this thesis two types of memory processes are studied: i) the recall of old memories which were formed before the immunoablation of the NMDAR and ii) the formation of new memories during and after the immunoablation. Results show that in the mouse model of cerebroventricular transfer of antibodies from patients with anti-NMDAR encephalitis, the antibodies cause memory impairment in forming new spatial memories as well as in recalling previously learned ones, but old memories are less susceptible to antibody-mediated changes than newly learned memories. The primary effect of NMDAR antibodies on the neural firing of hippocampal CA1 cells is hyperactivity due to an excitation-inhibition imbalance that lasts beyond the neurological recovery reported in other studies. The neuronal hyperactivity caused by NMDAR antibodies distorts place-fields, increases the noise in the entire population of CA1 cells, degrades spatial information, and leads to lower stability of mnemonic-related neuronal activity.