Zahid Padamsey

Two sides to long-term potentiation: a view towards reconciliation.

Almost since the discovery of long-term potentiation (LTP) in the hippocampus, its locus of expression has been debated. Throughout the years, convincing evidence has accumulated to suggest that LTP can be supported either presynaptically, by an increase in transmitter release, or postsynaptically, by an increase in α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor number. However, whereas postsynaptic enhancement appears to be consistently obtained across studies following LTP induction, presynaptic enhancement is not as reliably observed. Such discrepancies, along with the failure to convincingly identify a retrograde messenger required for presynaptic change, have led to the general view that LTP is mainly supported postsynaptically, and certainly, research within the field for the past decade has been heavily focused on the postsynaptic locus. Here, we argue that LTP can be expressed at either synaptic locus, but that pre- and postsynaptic forms of LTP are dissociable phenomena mediated by distinct mechanistic processes, which are sensitive to different patterns of neuronal activity. This view of LTP helps to reconcile discrepancies across the literature and may put to rest a decades-long debate.

Activity-Dependent Exocytosis of Lysosomes Regulates the Structural Plasticity of Dendritic Spines.

Summary Lysosomes have traditionally been viewed as degradative organelles, although a growing body of evidence suggests that they can function as Ca2+ stores. Here we examined the function of these stores in hippocampal pyramidal neurons. We found that back-propagating action potentials (bpAPs) could elicit Ca2+ release from lysosomes in the dendrites. This Ca2+ release triggered the fusion of lysosomes with the plasma membrane, resulting in the release of Cathepsin B. Cathepsin B increased the activity of matrix metalloproteinase 9 (MMP-9), an enzyme involved in extracellular matrix (ECM) remodelling and synaptic plasticity. Inhibition of either lysosomal Ca2+ signaling or Cathepsin B release prevented the maintenance of dendritic spine growth induced by Hebbian activity. This impairment could be rescued by exogenous application of active MMP-9. Our findings suggest that activity-dependent exocytosis of Cathepsin B from lysosomes regulates the long-term structural plasticity of dendritic spines by triggering MMP-9 activation and ECM remodelling.

Increased expression of dysbindin-1A leads to a selective deficit in NMDA receptor signaling in the hippocampus

The effects of the major schizophrenia susceptibility gene disease DTNBP1 on disease risk are likely to be mediated through changes in expression level of the gene product, dysbindin-1. How such changes might influence pathogenesis is, however, unclear. One possible mechanism is suggested by recent work establishing a link between altered dysbindin-1 expression and changes in surface levels of N-methyl-d-aspartate receptors (NMDAR), although neither the precise nature of this relationship, nor the mechanism underlying it, are understood. Using organotypic slices of rat hippocampus, we show that increased expression of dysbindin-1A in pyramidal neurons causes a severe and selective hypofunction of NMDARs and blocks induction of LTP. Cell surface, but not cytoplasmic, expression of the NR1 subunit of the NMDAR is decreased, suggesting dysregulation of NMDAR trafficking and, consistent with this, pharmacological inhibition of clathrin-dependent endocytosis is sufficient to reverse the deficit in NMDAR signaling. These results support the idea that the level of the NMDAR at the plasma membrane is modulated by changes in dysbindin-1 expression and offer further insight into the role of dysbindin-1 at an important cellular pathway implicated in schizophrenia.

Imaging synaptic plasticity

Over the past decade, the use and development of optical imaging techniques has advanced our understanding of synaptic plasticity by offering the spatial and temporal resolution necessary to examine long-term changes at individual synapses. Here, we review the use of these techniques in recent studies of synaptic plasticity and, in particular, long-term potentiation in the hippocampus.

Glutamate is required for depression but not potentiation of long-term presynaptic function

Hebbian plasticity is thought to require glutamate signalling. We show this is not the case for hippocampal presynaptic long-term potentiation (LTPpre), which is expressed as an increase in transmitter release probability (Pr). We find that LTPpre can be induced by pairing pre- and postsynaptic spiking in the absence of glutamate signalling. LTPpre induction involves a non-canonical mechanism of retrograde nitric oxide signalling, which is triggered by Ca2+ influx from L-type voltage-gated Ca2+ channels, not postsynaptic NMDA receptors (NMDARs), and does not require glutamate release. When glutamate release occurs, it decreases Pr by activating presynaptic NMDARs, and promotes presynaptic long-term depression. Net changes in Pr, therefore, depend on two opposing factors: (1) Hebbian activity, which increases Pr, and (2) glutamate release, which decreases Pr. Accordingly, release failures during Hebbian activity promote LTPpre induction. Our findings reveal a novel framework of presynaptic plasticity that radically differs from traditional models of postsynaptic plasticity.

Synaptic Transmission Optimization Predicts Expression Loci of Long-Term Plasticity

Summary Long-term modifications of neuronal connections are critical for reliable memory storage in the brain. However, their locus of expression—pre- or postsynaptic—is highly variable. Here we introduce a theoretical framework in which long-term plasticity performs an optimization of the postsynaptic response statistics toward a given mean with minimal variance. Consequently, the state of the synapse at the time of plasticity induction determines the ratio of pre- and postsynaptic modifications. Our theory explains the experimentally observed expression loci of the hippocampal and neocortical synaptic potentiation studies we examined. Moreover, the theory predicts presynaptic expression of long-term depression, consistent with experimental observations. At inhibitory synapses, the theory suggests a statistically efficient excitatory-inhibitory balance in which changes in inhibitory postsynaptic response statistics specifically target the mean excitation. Our results provide a unifying theory for understanding the expression mechanisms and functions of long-term synaptic transmission plasticity.

Inhibition of lysosomal Ca2+ signalling disrupts dendritic spine structure and impairs wound healing in neurons.

ABSTRACT A growing body of evidence suggests that lysosomes, which have traditionally been regarded as degradative organelles, can function as Ca2+ stores, regulated by the second messenger nicotinic acid adenine dinucleotide phosphate (NAADP). We previously demonstrated that in hippocampal pyramidal neurons, activity-dependent Ca2+ release from these stores triggers fusion of the lysosome with the plasma membrane. We found that the physiological role of this Ca2+-dependent fusion was to maintain the long-term structural enlargement of dendritic spines induced by synaptic activity. Here, we examined the pathophysiological consequences of lysosomal dysfunction in hippocampal pyramidal neurons by chronically inhibiting lysosomal Ca2+ signalling using the NAADP antagonist, NED-19. We found that within just 20 hours, inhibition of lysosomal function led to a profound intracellular accumulation of lysosomal membrane. This was accompanied by a significant change in dendritic spine structure, which included a lengthening of dendritic spines, an increase in the number of filipodia, and an overall decrease in spine number. Inhibition of lysosomal function also inhibited wound healing in neurons by preventing lysosomal fusion with the plasma membrane. Neurons were therefore more susceptible to injury. Our findings suggest that dysfunction in lysosomal Ca2+ signalling and lysosomal fusion with the plasma membrane may contribute to the loss of dendritic spines and neurons seen in neurological disorders, such as Niemann-Pick disease type C1, in which lysosomal function is impaired.

Imaging Synaptic Vesicles Using VGLUT1-Venus Knock-In Mice: Insights into the Dynamic Nature of Intersynaptic Vesicle Exchange

Traditionally, synapses have been regarded as compartmentalized nodes of communication, in which axonal boutons and dendritic spines operate independently of their neighbors and the efficacy of neurotransmission is regulated solely by patterned activity between presynaptic and postsynaptic cells.

Minimally invasive deep-brain imaging through a 50 μm-core multimode fibre.

Achieving optical access to deep-brain structures represents an important step towards the goal of understanding the mammalian central nervous system. The complex refractive index distribution within brain tissue introduces severe aberrations to long-distance light propagation thereby prohibiting image reconstruction using currently available non-invasive techniques. In an attempt to overcome this challenge endoscopic approaches have been adopted, principally in the form of fibre bundles or GRIN-lens based endoscopes. Unfortunately, these approaches create substantial mechanical lesions of the tissue precipitating neuropathological responses that include inflammation and gliosis. Together, lesions and the associated neuropathology may compromise neural circuit performance. By replacing Fourier-based image relay with a holographic approach, we have been able to reduce the volume of tissue lesion by more than 100-fold, while preserving diffraction-limited imaging performance. Here we demonstrate high-resolution fluorescence imaging of neuronal structures, dendrites and synaptic specialisations, in deep-brain regions of living mice. These results represent a major breakthrough in the compromise between high-resolution imaging and tissue damage, heralding new possibilities for deep-brain imaging in vivo.

Glutamate release is inhibitory and unnecessary for the long-term potentiation of presynaptic function

Long-term potentiation (LTP) and long-term depression (LTD) of transmitter release probability (Pr) are thought to be triggered by the activation of glutamate receptors. Here, we demonstrate that glutamate release at CA3-CA1 synapses is in fact inhibitory and unnecessary for increases in Pr. Instead, at active presynaptic terminals, postsynaptic depolarization alone can increase Pr by promoting the release of nitric oxide from neuronal dendrites in a manner dependent on L-type voltage-gated Ca2+ channels. The release of glutamate, in contrast, decreases Pr by activating presynaptic NMDA receptors (NMDAR). Thus, net changes in Pr are determined by the combined effect of both LTP-promoting and LTD-promoting processes, that is, by the amount of glutamate release and postsynaptic depolarization that accompany presynaptic activity, respectively. Neither of these processes directly depends on the activation of postsynaptic NMDARs. We further show that presynaptic changes can be captured by a simple mathematical framework, in which the role of presynaptic plasticity is to ensure that the ability for a presynaptic terminal to release glutamate is matched with its ability to predict postsynaptic spiking.