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PDE4 cyclic nucleotide phosphodiesterases reduce 3', 5' cAMP levels in the CNS and thereby regulate PKA activity and the phosphorylation of CREB, fundamental to depression, cognition, and learning and memory. The PDE4 isoform PDE4D5 interacts with the signaling proteins β-arrestin2 and RACK1, regulators of β 2 -adrenergic and other signal transduction pathways. Mutations in PDE4D in humans predispose to acrodysostosis, associated with cognitive and behavioral deficits. To target PDE4D5, we developed mice that express a PDE4D5-D556A dominant-negative transgene in the brain. Male transgenic mice demonstrated significant deficits in hippocampus-dependent spatial learning, as assayed in the Morris water maze. In contrast, associative learning, as assayed in a fear conditioning assay, appeared to be unaffected. Male transgenic mice showed augmented activity in prolonged (2 h) open field testing, while female transgenic mice showed reduced activity in the same assay. Transgenic mice showed no demonstrable abnormalities in prepulse inhibition. There was also no detectable difference in anxiety-like behavior, as measured in the elevated plus-maze. These data support the use of a dominant-negative approach to the study of PDE4D5 function in the CNS and specifically in learning and memory.

The prevalence of Alzheimer's disease (AD) is higher in females than in males, and causes more severe cognitive, memory and behavioral impairments. Previously, in male transgenic (Tg) APPSweDI mice, we reported that the novel lipophilic 1,4-dihydropyridine (DHP) derivative AP-12 crossed the blood-brain barrier, blocked neuronal and vascular calcium channels, changed brain protein expression and improved behavior. In this study, we used female Tg APPSweDI mice to assess the effects of AP-12 on behavior, and brain protein expression, with a particular focus on those of the GABAergic system. The results showed that in female Tg mice, similar to male Tg mice, AP-12 improved spatial learning/memory performance in the water maze test and demonstrated anxiolytic effect in the elevated zero maze (after single administration of AP-12) and elevated plus maze (after chronic injections of AP-12). In addition, we demonstrated upregulated expression of glutamate decarboxylase 67 (GAD67) and vesicular GABA transporter (VGAT) in the cingulate cortex and hippocampus, pointing to the role of the GABAergic system as one of the neural networks dysregulated in AD. In both female and male mice, AP-12 did not change the expression of hippocampal Homer-1, a protein which is involved in synaptic plasticity. However, in cingulate cortex, the staining density of Homer-1 was significantly increased in female mice. Further, female mice (similar to male mice) did not show changes in brain AChE expression and in the amyloid beta load in the hippocampus and cingulate cortex. In conclusion, the memory enhancing, anxiolytic and protein expression effects of AP-12 did not show sex specificity in APPSweDI mice. Considering the ability of AP-12 to block brain calcium channels and improve memory by enhancing the GABAergic and synaptic plasticity processes, AP-12 is a promising compound which merits further pre-clinical studies to investigate its usefulness in the treatment of AD., Competing Interests: statement None declared., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Ca2+ blockers, particularly those capable of crossing the blood-brain barrier (BBB), have been suggested as a possible treatment or disease modifying agents for neurodegenerative disorders, e.g., Alzheimer's disease. The present study investigated the effects of a novel 4-(N-dodecyl) pyridinium group-containing 1,4-dihydropyridine derivative (AP-12) on cognition and synaptic protein expression in the brain. Treatment of AP-12 was investigated in wild type C57BL/6J mice and transgenic Alzheimer's disease model mice (Tg APPSweDI) using behavioral tests and immunohistochemistry, as well as mass spectrometry to assess the blood-brain barrier (BBB) penetration. The data demonstrated the ability of AP-12 to cross the BBB, improve spatial learning and memory in both mice strains, induce anxiolytic action in transgenic mice, and increase expression of hippocampal and cortical proteins (GAD67, Homer-1) related to synaptic plasticity. The compound AP-12 can be seen as a prototype molecule for use in the design of novel drugs useful to halt progression of clinical symptoms (more specifically, anxiety and decline in memory) of neurodegenerative diseases, particularly Alzheimer's disease.

Spontaneously hypertensive rats (SHR) compared to normotensive rats display an accelerated decline in spatial learning and memory. However, few studies have systematically examined the independent contribution of hypertension vs. other age-related mechanisms to this decline. The present study uses a repeated acquisition water maze task to test the hypothesis that hypertension and/or the presence of angiotensin II can accelerate the age-related decrease of spatial learning and memory in rats. We have previously shown that both SHR and Wistar-Kyoto rats (WKY) display age-related decreases in spatial learning and memory; however, the rate of decline differs between the strains. The present results demonstrate that compared to young rats of the same strain, learning and memory in SHR declines significantly already at 12 months of age, and at 24 months of age both SHR and WKY rats are severely impaired in the water maze task. Lifetime treatment of either SHR or WKY with the antihypertensive drug captopril [an angiotensin converting enzyme (ACE) inhibitor] significantly attenuates the age-related impairment in learning and memory. In contrast, chronic treatment of SHR with captopril from 6 months of age only modestly decreases the decline in learning and memory. Whereas lifetime treatment with the vasodilator drug hydralazine also reduces arterial pressure in SHR, this treatment does not significantly preserve learning in 24-month-old SHR. Together, the data suggest captopril can delay the decline in spatial learning and memory in both aging SHR and WKY. Further, the results indicate that the memory enhancing effects of captopril are not primarily the due to the ability of captopril to lower blood pressure.

The anterior thalamic nuclei appear to play an important role in learning and memory. Connectionally and structurally, the lateral dorsal nucleus is similar to the anterior nuclei. This study tested the hypothesis that the laterodorsal thalamic nucleus (LD) also contributes to these functions. Adult Sprague-Dawley rats received bilateral ibotenic acid lesions of LD, and 2 weeks later the rats were tested in a repeated acquisition water maze task. The control groups displayed a short final escape latency and showed a preference for the correct quadrant in the probe trial. Rats with a lesion restricted to LD (LDL) were mildly impaired in the task, but rats with lesions that destroyed LD and also significantly (50%) damaged the adjacent anterior thalamic nuclei (LDL+) were severely impaired, displaying no improvement in performing the spatial task. In a second experiment, training in the same paradigm for 2 weeks resulted in improved final performance by LDL and control rats but not by LDL+ rats. These findings support the hypothesis that together with the anterior thalamic nuclei, LD plays a role in spatial learning and memory., (Copyright 2002 Elsevier Science B.V.)

Many studies have used repeated testing at different ages to study the age-related decline in learning and memory in animals. Generally, it has been assumed that performance is relatively independent of prior exposure(s). The present study tested the hypothesis that rats retain a significant memory of some aspects of spatial tasks for many months. Sprague-Dawley rats were trained in a repeated acquisition water maze task at 12 months of age, and retested in the same task at 24 months of age. Compared to 24-month-old naive rats, the pretrained rats initially performed significantly better on their first days of retesting at 24 months of age. In a second experiment, animals were trained for 2 weeks at 12 months of age and tested/retested for 2 weeks at the age of 24 months. Whereas the performance of the 24-month-old naive group improved over the 2 weeks of testing, the latencies of the pretrained animals were consistently shorter both initially, and throughout the testing. The performance of the pretrained rats in the second week of testing was similar to young rats. Together these data indicate that 24-month-old rats can learn spatial tasks well and that the performance of old rats in spatial tasks can be significantly influenced by prior exposure to that task, even 12 months earlier.

Transgenic mice carrying mutated human amyloid precursor protein (APPswe) and presenilin (PS1, A246E) genes develop first amyloid plaques around 9 months of age, but up to 18 months of age, amyloid depositions in these mice were largely restricted to the hippocampus, subiculum, and neocortex. To assess the behavioral consequences of amyloid accumulation in the hippocampal formation, we compared the effects of APP+PS1 (AP) genotype and fimbria-fornix (FFX) transection, either alone or combined, on various spatial learning and memory tasks. Both FFX-lesioned and AP mice were impaired in spatial navigation in the water maze, a typical hippocampal dependent task. Conversely, neither group of mice was impaired in a win-stay version of the radial arm maze (RAM) or position discrimination in the T-maze, tasks that do not depend on the hippocampus. FFX-lesioned mice were impaired in the win-shift version of the RAM, and in spontaneous and rewarded alternation in the T-maze, while AP mice performed equal to non-transgenic controls in all these working memory tasks, except long-term retention of the RAM task. AP mice thus appear to have a selective deficit in hippocampal dependent long-term memory, as do Alzheimer patients at early stage of the disease., (Copyright 2002 Elsevier Science B.V.)

This study tested the hypothesis that long-term hypertension impairs spatial learning and memory in rats. In 6-wk-old Sprague-Dawley rats, chronic hypertension was induced by placing one of three sizes of stainless steel clips around the descending aorta (above the renal artery), resulting in a 20-80-mm Hg increase of arterial pressure in all arteries above the clip, that is, the upper trunk and head. Ten months later, the rats were tested for 5 d in a repeated-acquisition water maze task, and on the fifth day, they were tested in a probe trial; that is, there was no escape platform present. At the end of the testing period, the nonsurgical and sham control groups had similar final escape latencies (16 +/- 4 sec and 23 +/- 9 sec, respectively) that were not significantly different from those of the three hypertensive groups. Rats with mild hypertension (140-160 mm Hg) had a final escape latency of 25 +/- 6 sec, whereas severely hypertensive rats (170-199 mm Hg) had a final escape latency of 21 +/- 7 sec and extremely hypertensive rats (>200 Hg) had a final escape latency of 19 +/- 5 sec. All five groups also displayed a similar preference for the correct quadrant in the probe trial. Together, these data suggest that sustained, severe hypertension for over 10 mo is not sufficient to impair spatial learning and memory deficits in otherwise normal rats.

Rats display an age-related impairment in learning and memory; however, few studies have systematically examined this relationship in multiple strains. The present study used a repeated acquisition water maze task to test the hypothesis that age-related decreases in learning and memory occur at different rates in three strains of rats, i.e. Sprague-Dawley (SD), spontaneously hypertensive (SHR), and Wistar Kyoto (WKY) rats. All three strains of rats displayed age-related decreases in spatial learning and memory; however, the rate of decline differed between the strains. Compared to young rats of the same strain, only SHR were significantly impaired at 12 months of age. All three strains displayed moderate impairment in learning the task at 18 months of age, and at 24 months of age all three strains of rats were severely impaired in the task, but SD performed best at 18 and 24 months of age. Further, SD and SHR displayed a probe trial bias at 3 months of age, but only SD had a bias at 12 months of age and none of the rats showed the bias at later ages. Thus, in these three strains, age-related impairment of spatial memory proceeds at different rates.

We investigated the effects of estrogen replacement therapy on water maze non-spatial and spatial navigation in mice. Three groups of mice were ovariectomized and two of these groups being implanted with s.c. pellets that produce blood levels of estrogen close to those found in estrous (estrogen low, 75-100 pg/ml blood) or proestrous (estrogen high, 300-400 pg/ml). The behavioral assessment was initiated 7 days after pellet implantation. Non-spatial navigation to a clearly visible platform was stimulated by low and high levels of estrogen. However, spatial navigation to a hidden platform was improved by low estrogen levels. We found that estrogen improves two different types of memory processes that depend on striatal (non-spatial navigation) and hippocampal (spatial) memory systems.

In very old, normotensive rats, a disorganization occurs selectively in the retrosplenial cortex, and a similar disorganization occurs in this area in spontaneously hypertensive rats (SHR) at a much earlier age. Since this breakdown compromises a neural circuit involved in learning and memory, this study tests the hypotheses that these functions are disturbed in mature SHR and that they can be prevented or attenuated by long-term, anti-hypertensive therapy. SHR and Sprague Dawley rats (SD) at 3- and 12 months of age, and a group of SHR that had been normotensive from 3 to 12 months of age (CAP-SHR) were trained on an 8 arm radial maze task. Of the 12-month-old groups, SD reached criterion earliest (28 +/- 2 days) and made the least number of total errors. In comparison, 12-month-old SHR took significantly longer to reach criterion (39 +/- 2 days) and made nearly twice as many total errors. CAP-SHR were intermediate between the other two groups (32 +/- 2 days). Three-month-old SD learned the task at the same rate as the 12-month-old SD. In contrast, 3-month-old SHR learned the task significantly faster (21 +/- 1 days) and with fewer errors than any other group. These data indicate that, in SHR, learning and memory are compromised by 12 months of age, and that anti-hypertensive therapy with captopril partially prevents this decline.

Mice carrying mutated human APPswe and PS1 (A246E) transgenes (A/P mice) show age-dependent memory impairment in hippocampus-dependent tasks. Moreover, the mice show normal learning in the water maze within a day but impairment across days. We recorded LTP in a slice preparation (CA1) and in chronically implanted animals (dentate gyrus, or DG) at 17–18 months of age. The genotypes did not differ in the basal synaptic transmission. Also, LTP induction and its maintenance over 60 min did not differ between A/P and control mice. However, the fEPSP enhancement in vivo decayed to 77% of its maximum in 24 h in A/P mice while remaining at 96% in control mice. The time course of the LTP decay in the A/P mice corresponds to their behavioral impairment and indicates that Aβ accumulation in the dentate gyrus may interfere with the signal transduction pathways responsible for memory consolidation. [Copyright &y& Elsevier]