Altered cognitive performance and synaptic function in the hippocampus of mice lacking C3

•C3 KO male mice show enhanced spatial learning despite reduced hippocampal neurogenesis.•Release probability of CA3-CA1 synapses is reduced in C3 KO mice.•Overall synaptic efficacy in the C3 KO hippocampus is unaltered.•C3 negatively regulates the number of hippocampal CA3-CA1 synapses.•C3 KO mice do not show spontaneous epileptiform activity in the hippocampus.

Previous work implicated the complement system in adult neurogenesis as well as elimination of synapses in the developing and injured CNS. In the present study, we used mice lacking the third complement component (C3) to elucidate the role the complement system plays in hippocampus-dependent learning and synaptic function. We found that the constitutive absence of C3 is associated with enhanced place and reversal learning in adult mice. Our findings of lower release probability at CA3-CA1 glutamatergic synapses in combination with unaltered overall efficacy of these synapses in C3 deficient mice implicate C3 as a negative regulator of the number of functional glutamatergic synapses in the hippocampus. The C3 deficient mice showed no signs of spontaneous epileptiform activity in the hippocampus. We conclude that C3 plays a role in the regulation of the number and function of glutamatergic synapses in the hippocampus and exerts negative effects on hippocampus-dependent cognitive performance.