Friend or Foe? The Varied Faces of Homeostatic Synaptic Plasticity in Neurodegenerative Disease.

Homeostatic synaptic plasticity (HSP) regulates synaptic strength both pre- and postsynaptically to ensure stability and efficient information transfer in neural networks. A number of neurological diseases have been associated with deficits in HSP, particularly diseases characterised by episodic network instability such as migraine and epilepsy. Recently, it has become apparent that HSP also plays a role in many neurodegenerative diseases. In this mini review, we present an overview of the evidence linking HSP to each of the major neurodegenerative diseases, finding that HSP changes in each disease appear to belong to one of three broad functional categories: (1) deficits in HSP at degenerating synapses that contribute to pathogenesis or progression; (2) HSP induced in a heterosynaptic or cell non-autonomous manner to support the function of networks of which the degenerating synapses or cells are part; and (3) induction of HSP within the degenerating population of synapses to preserve function and to resist the impact of synapse loss. Understanding the varied manifestations of HSP in neurodegeneration will not only aid understanding mechanisms of disease but could also inspire much-needed novel approaches to therapy.

Long-term depression links amyloid-ß to the pathological hyperphosphorylation of tau.

In Alzheimer's disease, soluble oligomers of the amyloid-ß peptide (Aßo) trigger a cascade of events that includes abnormal hyperphosphorylation of the protein tau, which is essential for pathogenesis. However, the mechanistic link between these two key pathological proteins remains unclear. Using hippocampal slices, we show here that an Aßo-mediated increase in glutamate release probability causes enhancement of synaptically evoked N-methyl-d-aspartate subtype glutamate receptor (NMDAR)-dependent long-term depression (LTD). We also find that elevated glutamate release probability is required for Aßo-induced pathological hyperphosphorylation of tau, which is likewise NMDAR dependent. Finally, we show that chronic, repeated chemical or optogenetic induction of NMDAR-dependent LTD alone is sufficient to cause tau hyperphosphorylation without Aßo. Together, these results support a possible causal chain in which Aßo increases glutamate release probability, thus leading to enhanced LTD induction, which in turn drives hyperphosphorylation of tau. Our data identify a mechanistic pathway linking the two critical pathogenic proteins of AD.

A Novel Optical Quantal Analysis of Miniature Events Reveals Enhanced Frequency Following Amyloid ß Exposure.

Non-evoked miniature release of neurotransmitters is increasingly recognized as playing an important role in neural function and is implicated in synaptic plasticity, metaplasticity, and homeostasis. Spontaneous miniature release events (minis) are usually measured electrophysiologically by recording the miniature postsynaptic currents (mEPSCs) that they evoke. However, this indirect technique can be confounded by changes within the postsynaptic neuron. Here, using the fluorescent probe SynaptopHluorin 2×, we have developed an optical method for the measurement of minis that enables direct assessment of release events. We use the technique to reveal that the frequency of minis following incubation of hippocampal neurons with Amyloid ß oligomers (Aßo) is increased. Electrophysiological mEPSC recordings obtained under the same conditions report a decrease in frequency, with the discrepancy likely due to Aßo-induced changes in quantal size. Optical quantal analysis of minis may therefore have a role in the study of minis in both normal physiology and disease, as it can circumvent potential confounds caused by postsynaptic changes.

Hippocampal mGluR1-dependent long-term potentiation requires NAADP-mediated acidic store Ca2+ signaling.

Acidic organelles, such as endosomes and lysosomes, store Ca2+ that is released in response to intracellular increases in the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). In neurons, NAADP and Ca2+ signaling contribute to synaptic plasticity, a process of activity-dependent long-term potentiation (LTP) [or, alternatively, long-term depression (LTD)] of synaptic strength and neuronal transmission that is critical for neuronal function and memory formation. We explored the function of and mechanisms regulating acidic Ca2+ store signaling in murine hippocampal neurons. We found that metabotropic glutamate receptor 1 (mGluR1) was coupled to NAADP signaling that elicited Ca2+ release from acidic stores. In turn, this released Ca2+-mediated mGluR1-dependent LTP by transiently inhibiting SK-type K+ channels, possibly through the activation of protein phosphatase 2A. Genetically removing two-pore channels (TPCs), which are endolysosomal-specific ion channels, switched the polarity of plasticity from LTP to LTD, indicating the importance of specific receptor store coupling and providing mechanistic insight into how mGluR1 can produce both synaptic potentiation and synaptic depression.

Health risk taking and human immunodeficiency virus risk in collegiate female athletes.

Risky health behaviors of female intercollegiate varsity athletes and their nonathlete peers were compared. Five hundred seventy-one female university students (109 athletes and 462 nonathlete peers) at two midwestern universities completed a self-administered, anonymous questionnaire during team meetings or class sessions. Each athlete was matched with two nonathlete controls of similar age, ethnicity, and class year to test for dichotomous outcome variables. A human immunodeficiency virus (HIV) risk scale was developed to identify factors associated with increased HIV risk for all of the female participants. Measures of alcohol and other drug use were associated with HIV risk. The athletes were found to engage in significantly fewer risk-taking behaviors than the nonathletes and to be at less risk for HIV. High levels of risk behaviors generally indicated the need for increased efforts to change risky behaviors in all college women.

Substance use and other health risk behaviors in collegiate athletes.

OBJECTIVES: To (a) determine the prevalence of alcohol and other drug use, and health risk behaviors among a general university population; and (b) compare health risk-taking behaviors between genders, and varsity athletes and their non-athlete peers. DESIGN: Descriptive survey of multiple health risk behaviors, including physical, mental health, alcohol and other drug, and sexual risk taking. SETTING: Two large midwestern universities. PARTICIPANTS: A convenience sample of 86% of 1,210 eligible students (271 athletes and 775 nonathlete peers) completed a self-administered, anonymous questionnaire during team meetings or class sessions. INTERVENTION: None. MAIN OUTCOME MEASURES: Differences between gender and athlete status were assessed using Cochran-Mantel-Haenszel statistics for the following variables, determined by questionnaire responses: physical risk, mental health, alcohol and other drug use, and sexual behaviors. RESULTS: Common risk behaviors in the entire collegiate sample included riding in a car with a driver who was under the influence of alcohol, driving and swimming under the influence of alcohol, binge drinking, and low rate of condom use for all types of sexual intercourse. Risk-taking behaviors varied by gender, with men showing more risk behaviors than women, except for suicide and sexual behaviors. Male athletes had a higher prevalence of risk behaviors than their male nonathlete counterparts, in contrast to female athletes, who had fewer risk behaviors than their female nonathlete counterparts. CONCLUSION: In contrast to previous studies, results of the present study show, when results are stratified by gender, that not all athletes engage more frequently than nonathletes in high risk behaviors. Results suggest that educational and early intervention strategies to decrease risk may need to be tailored according to gender and athletic status.