Philip Regan

Microtubule-associated protein tau is essential for long-term depression in the hippocampus

The microtubule-associated protein tau is a principal component of neurofibrillary tangles, and has been identified as a key molecule in Alzheimers disease and other tauopathies. However, it is unknown how a protein that is primarily located in axons is involved in a disease that is believed to have a synaptic origin. To investigate a possible synaptic function of tau, we studied synaptic plasticity in the hippocampus and found a selective deficit in long-term depression (LTD) in tau knockout mice in vivo and in vitro, an effect that was replicated by RNAi knockdown of tau in vitro. We found that the induction of LTD is associated with the glycogen synthase kinase-3-mediated phosphorylation of tau. These observations demonstrate that tau has a critical physiological function in LTD.

Tau phosphorylation at serine 396 residue is required for hippocampal LTD

Tau is required for the induction of long-term depression (LTD) of synaptic transmission in the hippocampus. Here we probe the role of tau in LTD, finding that an AMPA receptor internalization mechanism is impaired in tau KO mice, and that LTD causes specific phosphorylation at the serine 396 and 404 residues of tau. Surprisingly, we find that phosphorylation at serine 396, specifically, is critical for LTD but has no role in LTP. Finally, we show that tau KO mice exhibit deficits in spatial reversal learning. These findings underscore the physiological role for tau at the synapse and identify a behavioral correlate of its role in LTD.

Acute stress causes rapid synaptic insertion of Ca2+-permeable AMPA receptors to facilitate long-term potentiation in the hippocampus

The neuroendocrine response to episodes of acute stress is crucial for survival whereas the prolonged response to chronic stress can be detrimental. Learning and memory are particularly susceptible to stress with cognitive deficits being well characterized consequences of chronic stress. Although there is good evidence that acute stress can enhance cognitive performance, the mechanism(s) for this are unclear. We find that hippocampal slices, either prepared from rats following 30 min restraint stress or directly exposed to glucocorticoids, exhibit an N-methyl-d-aspartic acid receptor-independent form of long-term potentiation. We demonstrate that the mechanism involves an NMDA receptor and PKA-dependent insertion of Ca2+-permeable AMPA receptors into synapses. These then trigger the additional NMDA receptor-independent form of LTP during high frequency stimulation.

Translational concepts of mGluR5 in synaptic diseases of the brain

The G-protein coupled receptor family of glutamate receptors, termed metabotropic glutamate receptors (mGluRs), are implicated in numerous cellular mechanisms ranging from neural development to the processing of cognitive, sensory, and motor information. Over the last decade, multiple mGluR-related signal cascades have been identified at excitatory synapses, indicating their potential roles in various forms of synaptic function and dysfunction. This review highlights recent studies investigating mGluR5, a subtype of group I mGluRs, and its association with a number of developmental, psychiatric, and senile synaptic disorders with respect to associated synaptic proteins, with an emphasis on translational pre-clinical studies targeting mGluR5 in a range of synaptic diseases of the brain.

Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus

The acute neurotoxicity of oligomeric forms of amyloid-β 1-42 (Aβ) is implicated in the pathogenesis of Alzheimer’s disease (AD). However, how these oligomers might first impair neuronal function at the onset of pathology is poorly understood. Here we have examined the underlying toxic effects caused by an increase in levels of intracellular Aβ, an event that could be important during the early stages of the disease. We show that oligomerised Aβ induces a rapid enhancement of AMPA receptor-mediated synaptic transmission (EPSCA) when applied intracellularly. This effect is dependent on postsynaptic Ca2+ and PKA. Knockdown of GluA1, but not GluA2, prevents the effect, as does expression of a S845-phosphomutant of GluA1. Significantly, an inhibitor of Ca2+-permeable AMPARs (CP-AMPARs), IEM 1460, reverses the increase in the amplitude of EPSCA. These results suggest that a primary neuronal response to intracellular Aβ oligomers is the rapid synaptic insertion of CP-AMPARs.

Physiological and Pathophysiological Implications of Synaptic Tau

Tauopathies encompass a broad range of neurodegenerative diseases featuring extensive neuronal death and cognitive decline. However, research over the past 30 years has failed to significantly advance our understanding of how tau causes dementia, limiting the design of rational therapeutics. It has become evident that we need to expand our understanding of tau in physiology, in order to delineate how tau may contribute to pathology. This review discusses recent evidence that has uncovered a novel aspect of tau function, based on its previously uncharacterized localization to the synapse. Here, multiple streams of evidence support a critical role for synaptic tau in the regulation of synapse physiology. In particular, long-term depression, a form of synaptic weakening, is dependent on the presence of tau in hippocampal neurons. The regulation of tau by specific phosphorylation events downstream of GSK-3β activation appears to be integral to this signaling role. We also describe how the regulation of synapse physiology by tau and its phosphorylation may inform our understanding of tauopathies and comorbid diseases. This work should provide a platform for future tau biology research in addition to therapeutic design.

The role of neuronal calcium sensors in balancing synaptic plasticity and synaptic dysfunction.

Neuronal calcium sensors (NCS) readily bind calcium and undergo conformational changes enabling them to interact and regulate specific target molecules. These interactions lead to dynamic alterations in protein trafficking that significantly impact upon synaptic function. Emerging evidence suggests that NCS and alterations in Ca2+ mobilization modulate glutamate receptor trafficking, subsequently determining the expression of different forms of synaptic plasticity. In this review, we aim to discuss the functional relevance of NCS in protein trafficking and their emerging role in synaptic plasticity. Their significance within the concept of “translational neuroscience” will also be highlighted, by assessing their potential as key molecules in neurodegeneration.

Ca2+-permeable AMPA receptor: A new perspective on amyloid-beta mediated pathophysiology of Alzheimer's disease

ABSTRACT &agr;‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid receptors (AMPARs) are the primary conduits of excitatory synaptic transmission. AMPARs are predominantly Ca2+‐impermeable in the matured excitatory synapse, except under certain circumstances. Growing evidence implicates the Ca2+ permeability of AMPARs in the regulation of long‐term synaptic plasticity and in the pathophysiology of several neurological disorders. Therefore, the Ca2+ conductance of AMPARs may have both physiological and pathological roles at synapses. However, our understanding of the role of Ca2+ permeable AMPARs (CP‐AMPARs) in Alzheimers disease is limited. Here we discuss insights into the potential CP‐AMPAR mediated pathophysiology of Alzheimers disease, including: 1. Ca2+‐mediated aberrant regulation of synapse weakening mechanisms, and 2. neuronal network dysfunction in the brain. Consideration of CP‐AMPARs as primary drivers of pathophysiology could help in understanding synaptopathologies, and highlights the potential of CP‐AMPARs as therapeutic targets in Alzheimers disease. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’.

Glucocorticoids activate a synapse weakening pathway culminating in tau phosphorylation in the hippocampus

ABSTRACT Evidence suggests that the stress hormones glucocorticoids (GCs) can cause cognitive deficits and neurodegeneration. Previous studies have found GCs facilitate physiological synapse weakening, termed long‐term depression (LTD), though the precise mechanisms underlying this are poorly understood. Here we show that GCs activate glycogen synthase kinase‐3 (GSK‐3), a kinase crucial to synapse weakening signals. Critically, this ultimately leads to phosphorylation of the microtubule associated protein tau, specifically at the serine 396 residue, and this is a causal factor in the GC‐mediated impairment of synaptic function. These findings reveal the link between GCs and synapse weakening signals, and the potential for stress‐induced priming of neurodegeneration. This could have important implications for our understanding of how stress can lead to neurodegenerative disease.

Cyclin Y inhibits plasticity-induced AMPA receptor exocytosis and LTP.

Cyclin Y (CCNY) is a member of the cyclin protein family, known to regulate cell division in proliferating cells. Interestingly, CCNY is expressed in neurons that do not undergo cell division. Here, we report that CCNY negatively regulates long-term potentiation (LTP) of synaptic strength through inhibition of AMPA receptor trafficking. CCNY is enriched in postsynaptic fractions from rat forebrain and is localized adjacent to postsynaptic sites in dendritic spines in rat hippocampal neurons. Using live-cell imaging of a pH-sensitive AMPA receptor, we found that during LTP-inducing stimulation, CCNY inhibits AMPA receptor exocytosis in dendritic spines. Furthermore, CCNY abolishes LTP in hippocampal slices. Taken together, our findings demonstrate that CCNY inhibits plasticity-induced AMPA receptor delivery to synapses and thereby blocks LTP, identifying a novel function for CCNY in post-mitotic cells.