Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Enhances Hippocampal Synaptic Plasticity and Improves Memory Performance in Huntington's Disease

Mol Neurobiol. 2018 Nov;55(11):8263-8277. doi: 10.1007/s12035-018-0972-5. Epub 2018 Mar 10.


Deficits in hippocampal synaptic plasticity result in cognitive impairment in Huntington's disease (HD). Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that exerts neuroprotective actions, mainly through the PAC1 receptor. However, the role of PACAP in cognition is poorly understood, and no data exists in the context of Huntington's disease (HD). Here, we investigated the ability of PACAP receptor stimulation to enhance memory development in HD. First, we observed a hippocampal decline of all three PACAP receptor expressions, i.e., PAC1, VPAC1, and VPAC2, in two different HD mouse models, R6/1 and HdhQ7/Q111, from the onset of cognitive dysfunction. In hippocampal post-mortem human samples, we found a specific decrease of PAC1, without changes in VPAC1 and VPAC2 receptors. To determine whether activation of PACAP receptors could contribute to improve memory performance, we conducted daily intranasal administration of PACAP38 to R6/1 mice at the onset of cognitive impairment for seven days. We found that PACAP treatment rescued PAC1 level in R6/1 mice, promoted expression of the hippocampal brain-derived neurotrophic factor, and reduced the formation of mutant huntingtin aggregates. Furthermore, PACAP administration counteracted R6/1 mice memory deficits as analyzed by the novel object recognition test and the T-maze spontaneous alternation task. Importantly, the effect of PACAP on cognitive performance was associated with an increase of VGlut-1 and PSD95 immunolabeling in hippocampus of R6/1 mice. Taken together, these results suggest that PACAP, acting through stimulation of PAC1 receptor, may have a therapeutic potential to counteract cognitive deficits induced in HD.

Keywords: Hippocampus; Huntington’s disease; PAC1; PACAP; Synaptic plasticity.

MeSH terms

  • Administration, Intranasal
  • Animals
  • Brain-Derived Neurotrophic Factor / metabolism
  • Cognition Disorders / physiopathology
  • Disease Models, Animal
  • Disks Large Homolog 4 Protein / metabolism
  • Gene Expression Regulation / drug effects
  • Hippocampus / pathology
  • Hippocampus / physiopathology*
  • Humans
  • Huntingtin Protein / metabolism
  • Huntington Disease / physiopathology*
  • Male
  • Memory / physiology*
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Neuronal Plasticity / drug effects*
  • Pituitary Adenylate Cyclase-Activating Polypeptide / administration & dosage
  • Pituitary Adenylate Cyclase-Activating Polypeptide / pharmacology*
  • Protein Aggregates
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide / metabolism
  • Vesicular Glutamate Transport Protein 1 / metabolism


  • Brain-Derived Neurotrophic Factor
  • Disks Large Homolog 4 Protein
  • Dlg4 protein, mouse
  • Huntingtin Protein
  • Pituitary Adenylate Cyclase-Activating Polypeptide
  • Protein Aggregates
  • Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
  • Slc17a7 protein, mouse
  • Vesicular Glutamate Transport Protein 1