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

Abstract

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.

Meridianins and Lignarenone B as Potential GSK3β Inhibitors and Inductors of Structural Neuronal Plasticity

“…To evaluate possible effects of meridianins and lignarenone B in neuronal structural plasticity, primary cortical neurons were treated at 4DIV with 10 µM of these marine molecules (highest dose) since it was the dose of meridianins with the best GSK3βinhibition capacity. As we previously described for this type of in vitro approach [70,81,82], three days after the treatment we analysed morphological characteristics of the imaged neurons stained for MAP2 by using the Sholl analysis (Figure 7). The results of meridianins, indicated that the number of intersections in the treated cultures were increased compared with the non-treated condition (two-way ANOVA analysis; interaction effect, number of dendrites, F 7, 536 = 55.91, p < 0.0001) ( Figure 7A,B).…”

The Potential Role of Gut Peptide Hormones in Autism Spectrum Disorder

“…In addition, studies are gradually revealing the modulatory function of PACAP in neurodevelopment and neuroprotection, which might give further explanation for its involvement in ASD, which is one neurodevelopmental disorder. As further evidence, PACAP can stimulate the growth of both axons (Ogata et al, 2015) and dendritic spines (Cabezas-Llobet et al, 2018) under normal or disease conditions. Moreover, PACAP receptor PAC1 also mediates the differentiation and migration of cortical neuronal progenitors (Adnani et al, 2015).…”

“…Electrophysiological studies reveal that PACAP improves synaptic plasticity in mouse hippocampus (Cabezas-Llobet et al, 2018), and increases both frequency and amplitude of excitatory postsynaptic currents (EPSCs) of autonomic synapse (Starr and Margiotta, 2017), giving clues of how PACAP is involved in the autism-related behaviors. In addition, studies are gradually revealing the modulatory function of PACAP in neurodevelopment and neuroprotection, which might give further explanation for its involvement in ASD, which is one neurodevelopmental disorder.…”

Pituitary Adenylate Cyclase Activating Polypeptide Elicits Neuroprotection Against Acute Ischemic Neuronal Cell Death Associated with NMDA Receptors

“…These observations indicated that PACAP-27/38 enhanced neuroprotection against acute ischemic stroke via increased expression of neurotrophic factors [28]. Additionally, delivering PACAP38 intranasally in Huntington's disease mouse models mitigated disease-related deficits by restoring cognitive function and PAC1R protein levels, and increasing expression of BDNF and proteins associated with synaptic plasticity [29]. PACAP increases its own expression in an autocrine positive feedback loop [30].…”