Multiple sclerosis (MS) is a devastating demyelinating disease of the central nervous system (CNS), characterised by white matter lesions, inflammation, and axonal degeneration.Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are endogenous neuropeptides whose signalling is mediated by three G-protein coupled receptors: PAC1, VPAC1 and VPAC2. While these neuropeptides are known for their neuroprotective and anti-inflammatory activities in the CNS, their role in preventing demyelination, neuronal degeneration and neuroinflammation is unclear. This study examines the therapeutic potential of PACAP, VIP and PAC1 agonist Maxadilan using the cuprizone model of MS. Experiments demonstrated robust improvements of neurological scores, locomotion, and coordination in 0.2% cuprizone-fed C57BL/6 mice treated with PACAP, VIP or Maxadilan (5nmol/kg I.P; n=12/group). At a molecular level, PACAP and Maxadilan, but not VIP, preserved myelin integrity, diminished glial cell activation, and maintained synapse levels in the white matter, suggesting a PAC1-specific protective effect in the CNS under demyelinating conditions. In addition, to define the neuron-specific contribution of PAC1 in the CNS, we studied hippocampal-dependent memory function in a conditional/inducible mouse model harbouring PAC1 gene deletion in CamK2a+ neurons (CamK2a-creERT+/- PAC1-flox/flox). Our findings show that loss of PAC1 in CamK2a+ neurons caused spatial memory impairment, alongside increased expression of neuronal nitric oxide synthase (nNOS) and glutamic acid decarboxylase 65 (GAD2) in the hippocampus. Altogether, data demonstrates that targeting PAC1 is protective/anti-inflammatory during experimental demyelination. Moreover, neuronal PAC1 seems to play an essential role in spatial memory, likely via its activities on synaptic functioning and/or neurotransmitter trafficking.