Importance of Full-Collapse Vesicle Exocytosis for Synaptic Fatigue-Resistance at Rat Fast and Slow Muscle Neuromuscular Junctions.

Neurotransmitter release during trains of activity usually involves two vesicle pools (readily releasable pool, or RRP, and reserve pool, or RP) and two exocytosis mechanisms ("full-collapse" and "kiss-and-run"). However, synaptic terminals are adapted to differing patterns of use and the relationship of these factors to enabling terminals to adapt to differing transmitter release demands is not clear. We have therefore tested their contribution to a terminal's ability to maintain release, or synaptic fatiguability in motor terminals innervating fast-twitch (fatiguable), and postural slow-twitch (fatigue-resistant) muscles.

Mutant Tau knock-in mice display frontotemporal dementia relevant behaviour and histopathology.

Models of Tau pathology related to frontotemporal dementia (FTD) are essential to determine underlying neurodegenerative pathologies and resulting tauopathy relevant behavioural changes. However, existing models are often limited in their translational value due to Tau overexpression, and the frequent occurrence of motor deficits which prevent comprehensive behavioural assessments. In order to address these limitations, a forebrain-specific (CaMKIIα promoter), human mutated Tau (hTauP301L+R406W) knock-in mouse was generated out of the previously characterised PLB1Triple mouse, and named PLB2Tau.

Age-dependent changes in hippocampal synaptic transmission and plasticity in the PLB1Triple Alzheimer mouse.

Several genetically engineered models exist that mimic aspects of the pathological and cognitive hallmarks of Alzheimer's disease (AD). Here we report on a novel mouse model generated by targeted knock-in of transgenes containing mutated human amyloid precursor protein (APP) and microtubule-associated protein tau genes, inserted into the HPRT locus and controlled by the CaMKIIα regulatory element. These mice were crossed with an asymptomatic presenilin1A246E overexpressing line to generate PLB1Triple mice.

Abnormal cognition, sleep, EEG and brain metabolism in a novel knock-in Alzheimer mouse, PLB1.

Late-stage neuropathological hallmarks of Alzheimer's disease (AD) are β-amyloid (βA) and hyperphosphorylated tau peptides, aggregated into plaques and tangles, respectively. Corresponding phenotypes have been mimicked in existing transgenic mice, however, the translational value of aggressive over-expression has recently been questioned. As controlled gene expression may offer animal models with better predictive validity, we set out to design a transgenic mouse model that circumvents complications arising from pronuclear injection and massive over-expression, by targeted insertion of human mutated amyloid and tau transgenes, under the forebrain- and neurone-specific CaMKIIα promoter, termed PLB1(Double).

The cholinergic system and hippocampal plasticity.

Acetylcholine is an essential excitatory neurotransmitter in the central nervous system and undertakes a vital role in cognitive function. Consequently, there is ample evidence to suggest the involvement of both nicotinic and muscarinic acetylcholine receptors in the modulation of synaptic plasticity, which is believed to be the molecular correlate of learning and memory. In the hippocampus in particular, multiple subtypes of both nicotinic and muscarinic receptors are present at presynaptic and postsynaptic loci of both principal neurons and inhibitory interneurons, where they exert profound bi-directional influences on synaptic transmission.

Aluminum does not enhance beta-amyloid toxicity in rat hippocampal cultures.

A number of environmental factors have been implicated in neurodegenerative disorders, including metallotoxins such as aluminum (Al). In the present study, the toxicity of Al-quinate (AlQ), a well-characterized Al complex, was investigated in primary rat hippocampal cultures in comparison to inorganic Al (Al-S). AlQ was significantly less toxic than Al-S during both short- (3h) and long-term (24h) incubations.

Aluminium interferes with hippocampal calcium signaling in a species-specific manner.

Aluminium (Al) has been implicated in a number of neurodegenerative disorders and the disruption of calcium homeostasis has been proposed as a possible mechanism. To investigate ligand- and structure-specific effects of Al species, calcium imaging was used to probe the influence of five Al complexes - in comparison to inorganic Al (Al-S) - on N-methyl d-aspartate receptor (NMDAR) and voltage-dependent calcium channel (VDCC) function in hippocampal neurontos. The Al complexes utilized comprised three Al-citrate species (AlCit1-3), Al-quinate (AlQ) and Al-N-phosphonomethyliminodiacetate (AlNTAP).

The seed extract of Cassia obtusifolia offers neuroprotection to mouse hippocampal cultures.

The precise causative factors in neurodegenerative diseases such as Alzheimer's (AD) and Parkinson's disease remain elusive, but mechanisms implicated comprise excitotoxicity, mitochondrial dysfunction, and in the case of AD, the amyloid beta peptide (Abeta). Current therapeutic strategies for such disorders are very limited; thus, traditional herbal medicines currently receive increased attention. The seeds of Cassia obtisufolia have long been used in traditional eastern medicine and more recently the ethanolic fraction of the seeds (COE) has been shown to attenuate memory impairments in mice.

Memantine acts as a cholinergic stimulant in the mouse hippocampus.

The non-competitive NMDA receptor antagonist memantine, currently prescribed for the treatment of Alzheimer's disease, is assumed to prevent the excitotoxicity implicated in neurodegenerative processes. Here, we investigated the actions of memantine on hippocampal function and signalling. In behavioural experiments using the water maze, we observed that memantine (at 2 mg/kg) reversed scopolamine-induced learning deficits in mice.

Differential toxicity of novel aluminium compounds in hippocampal culture.

The dependence of aluminium (Al) toxicity on its chemical form has been implicated in previous studies, but the complex chemistry of Al in solutions of biological preparations has hampered a reliable assessment. Here, we assessed the toxicity of select and pure Al(III) citrate compounds, well-characterized at physiological pH, and compared it with Al from standard solution (in HCl). Cell death rates of neurones and glia were established in hippocampal cultures following 3h incubations in a HEPES-buffered solution and 24h incubations in full culture medium.