Non-technical summary The sizes of neurons and their synaptic connections are regulated by multiple molecular mechanisms to provide neuronal networks that perform well-defined functions. Deletion of the tumour suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) during early development leads to a 2-to 3-fold increase in neuronal and synaptic size and abnormalities in synaptic plasticity, the cellular mechanism underlying learning and memory. Whether PTEN deletion affects synaptic plasticity directly or as a consequence of its effect on the neuronal and synaptic size remained unclear. Here we show that deletion of the Pten gene in mice during postnatal development, when the central nervous system is formed, does not affect neuronal or synaptic size but impairs synaptic plasticity. Thus, PTEN affects neuronal structure and synaptic plasticity through independent mechanisms. Abstract The tumour suppressor PTEN is the central negative regulator of the phosphatidylinositol 3-kinase (PI3K) signalling pathway, which mediates diverse processes in various tissues. In the nervous system, the PI3K pathway modulates proliferation, migration, cellular size, synaptic transmission and plasticity. In humans, neurological abnormalities such as autism, seizures and ataxia are associated with inherited PTEN mutations. In rodents, Pten loss during early development is associated with extensive deficits in neuronal migration and substantial hypertrophy of neurons and synaptic densities; however, whether its effect on synaptic transmission and plasticity is direct or mediated by structural abnormalities remains unknown. Here we analysed neuronal and synaptic structures and function in Pten-conditional knockout mice in which the gene was deleted from excitatory neurons postnatally. Using two-photon imaging, Golgi staining, immunohistochemistry, electron microscopy, and electrophysiological tools, we determined that Pten loss does not affect hippocampus development, neuronal or synaptic structures, or basal excitatory synaptic transmission. However, it does cause deficits in both major forms of synaptic plasticity, long-term potentiation and long-term depression, of excitatory synaptic transmission. These deficits coincided with impaired spatial memory, as measured in water maze tasks. Deletion of Pdk1, which encodes a positive downstream regulator of the PI3K pathway, rescued Pten-mediated deficits in synaptic plasticity but not in spatial memory. These results suggest that PTEN independently modulates functional and structural properties of hippocampal neurons and is directly involved in mechanisms of synaptic plasticity.

The 5-Lipoxygenase (5LO) is upregulated in Alzheimer’s disease (AD), and in vivo modulates the amyloidotic phenotype of APP transgenic mice. However, no data are available on the effects that 5LO has on synaptic function, integrity and cognition. To address this issue we used a genetic and a pharmacologic approach by generating 3xTg mice deficient for 5LO, and administering 3xTg mice which a 5LO inhibitor. Compared with controls, we found that even before the development of overt neuropathology, both animals manifested significant memory improvement, rescue of their synaptic dysfunction and amelioration of synaptic integrity. In addition, later in life these mice had a significant reduction of Aβ and tau pathology.Our findings support a novel functional role for 5LO in regulating synaptic plasticity and memory. They establish this proetin as a pleiotropic contributor to the development of the full spectrum of the AD phenotype, making it a valid therapeutic target for the treatment of AD.

Background The 5-lipoxygenase (5LO) is a protein widely distributed in the central nervous system where modulates amyloidosis and memory impairments in transgenic mouse models of Alzheimer’s disease. However, no data are available as to whether 5LO is elevated in human tauopathy, or if it directly influences tau pathology in a relevant model of the disease. Methods We assayed 5LO levels in brain samples from tauopathy patients and transgenic tau mice, and evaluated the effect that 5LO pharmacological inhibition has on the phenotype of these mice. Results The 5LO is up-regulated in human tauopathy and transgenic tau mice brains. Pharmacological blockade of 5LO in tau mice results in significant memory improvement, rescue of synaptic integrity and dysfunction, and reduction of tau pathology via a cdk5-dependent mechanism. Conclusions Our results establish 5LO as a key player in the development of the tau pathology phenotype, and a novel viable therapeutic target for the pharmacological treatment of human tauopathy.

Emerging evidence indicates the involvement of GPR55 and its proposed endogenous ligand, lysophosphatidylinositol (LPI), in nociception, yet their role in central pain processing has not been explored. Using Ca 21 imaging, we show here that LPI elicits concentration-dependent and GPR55-mediated increases in intracellular Ca 21 levels in dissociated rat periaqueductal gray (PAG) neurons, which express GPR55 mRNA. This effect is mediated by Ca 21 release from the endoplasmic reticulum via inositol 1,4,5-trisphosphate receptors and by Ca 21 entry via P/Q-type of voltage-gated Ca 21 channels. Moreover, LPI depolarizes PAG neurons and upon intra-PAG microinjection, reduces nociceptive threshold in the hot-plate test. Both these effects are dependent on GPR55 activation, because they are abolished by pretreatment with antagonist. Thus, we provide the first pharmacological evidence that GPR55 activation at central levels is pronociceptive, suggesting that interfering with GPR55 signaling in the PAG may promote analgesia.

Background 5-lipoxygenase activating protein (FLAP) is abundantly present in the central nervous system. Although its function has been extensively interrogated in the context of peripheral inflammation, novel roles for this protein are emerging in the central nervous system. The objective of our study was to investigate the functional role that FLAP plays in a mouse model of Alzheimer’s disease (AD) with plaques and tangles (i.e., 3×Tg mice). Methods By implementing a genetic knockout of FLAP and pharmacologic inhibition with a FLAP inhibitor (MK-591), we evaluated the effect on the AD-like neuropathology, cognition, and synaptic plasticity in the 3×Tg mice. Results We show that reduction of FLAP leads to amelioration of cognition and memory along with the rescuing of synaptic dysfunction at an early age before the development of overt neuropathology. Genetic knockout and pharmacologic inhibition of FLAP also yielded an improvement in AD pathology through a reduction in Aβ via the γ-secretase pathway and a decrease in tau phosphorylation through the cdk5 pathway. Conclusions Our studies identify a novel functional role for FLAP in regulating memory and synaptic plasticity. They establish this protein at the crossroad of multiple pathways that ultimately contribute to the development of the entire AD-like phenotype, making it a viable therapeutic target with disease-modifying capacity for the treatment of this disease.

Although the initial events of Alzheimer's disease (AD) are still not known, it is clear that the disease in its sporadic form results from the combination of genetic and environmental risk factors. Among the latter, behavioral stress has been increasingly recognized as an important factor in the propagation of AD. However, the mechanisms underlying this modulation remain to be fully investigated. Since stress up-regulates the ALOX5 gene product, 5-lipoxygenase (5LO), herein we investigated its role in modulating stress-dependent development of the AD phenotype. To reach this goal, triple transgenic (3xTg) mice and 3xTg genetically deficient for 5LO were investigated after undergoing a restraint/isolation paradigm. In the present paper, we found that 28 days of restraint/isolation stress worsened tau phosphorylation and solubility, increased glycogen synthase kinase 3β activity, compromised long-term potentiation and impaired fear-conditioned memory recall in 3xTg animals, but not in 3xTg animals lacking 5LO (3xTg/5LO-/-). These results highlight the novel functional role that the ALOX5 gene plays in the development of the biochemical, electrophysiological and behavioral sequelae of stress in the AD context. They provide critical support that this gene and its expressed protein are viable therapeutic targets to prevent the onset or delay the progression of AD in individuals exposed to this risk factor.

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