To investigate the molecular basis of memory dysfunction in multiple sclerosis (MS)

Memory dysfunction in MS is thought to reflect loss of synapses in the hippocampus, but its molecular basis remains unknown. Components of the complement system, C1q and C3, can mediate elimination of synapses and we have previously shown that complement C1q/C3 tags synapses in the MS hippocampus.

We found that C1q/C3 deposits are highest in the CA2 subfield of the MS hippocampus, concomitant to an enrichment (~2-fold of controls) in the excitatory presynaptic vesicular glutamate transporter (vGlut-1) and its postsynaptic domain protein (PSD95) whereas  the inhibitory presynaptic vesicular GABA transporter (vGAT) (~2-fold of controls) and the postsynaptic scaffolding protein gephyrin (~7-fold of controls) were reduced. Clinico-pathological correlations showed that C1q deposits in CA2 were ~7-fold higher in patients with cognitive impairments and correlated negatively with hippocampal volume (Spearman correlation coefficient r = –058).

Similar to the findings in MS, cuprizone treatment caused a ~10-fold increase in C1q deposition with the largest change in CA2. Furthermore, while the presynaptic vGlut-1 marker was increased in CA2 (~30-fold of controls) the presynaptic vGAT was decreased (7-fold of controls). Electrophysiological recordings in acute brain slices demonstrated that the feed-forward inhibition from CA3 to CA2 pyramidal cells, via local GABA-ergic interneurons, was attenuated in cuprizone mice. Finally, consistent with the recent discovery that CA2 selectively encodes for social memory, we found that cuprizone-fed mice performed significantly worse in a social recognition test.

Demyelinating hippocampal lesions are associated with complement activation and pathway-specific pruning of inhibitory synapses but synaptogenesis of excitatory synapses, revealing an emerging critical role of the hippocampal CA2 subfield in MS.