Membrane glycoprotein M6a, together with M6b and proteolipid protein (PLP/DM20), belongs to the PLP family. M6a promotes neurite, axon, filopodium/spine and synapse formation in primary hippocampal neurons and cell lines. Altered M6a expression and genetic variants are linked with psychiatric disorders in human and animal models. However, the participation of M6a in physiological processes has not been established yet. Molecular cascades triggered by new experience induce synaptic plasticity and cell-wide alterations, critical for a new memory to consolidate. To study M6a’s role in memory processes, we injected the neutralizing M6a-mAb or an IgG isotype (control group) into the hippocampus after training in an inhibitory avoidance task in mice. Memory retention was tested at 3, 6 and 48 hours post-training and animals were sacrificed to evaluate synapse number in the hippocampus. Our results show that M6a-mAb administration immediately after training did not affect short-term memory (3 hours). On the other hand, we evidenced an involvement of M6a in long-term memory consolidation, as M6a-mAb injection significantly reduced task performance when mice were tested at 6 and 48 hours. This was accompanied by a decrease in synapse number in the CA1 region. Altogether, our results suggest that M6a is involved in memory consolidation and might play a key role on synaptic plasticity induced by learning.