Molecular neurobiologyMar 12, 2018

PACAP boosts memory and brain cell connections in the memory area in Huntington's disease

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Updated Apr 4, 2026

Abstract

All three PACAP receptors (PAC1, VPAC1, and VPAC2) showed a decline in expression in two different mouse models of Huntington's disease.

A specific decrease in PAC1 receptor expression was observed in hippocampal post-mortem human samples, with no changes in VPAC1 and VPAC2.
Daily intranasal administration of PACAP38 in R6/1 mice led to a recovery of PAC1 levels and promoted the expression of brain-derived neurotrophic factor.
PACAP treatment reduced the formation of mutant huntingtin aggregates in R6/1 mice.
Cognitive performance improvements were noted in R6/1 mice, as indicated by enhanced performance in memory tasks.
The positive effects of PACAP on cognition were associated with increased levels of VGlut-1 and PSD95 in the hippocampus.

Simplified

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.

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PACAP boosts memory and brain cell connections in the memory area in Huntington's disease

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