Neuronal surface P antigen (NSPA) modulates postsynaptic NMDAR stability through ubiquitination of tyrosine phosphatase PTPMEG

Abstract Background Cognitive dysfunction (CD) is common among patients with the autoimmune disease systemic lupus erythematosus (SLE). Anti-ribosomal P autoantibodies associate with this dysfunction and have neuropathogenic effects that are mediated by cross-reacting with neuronal surface P antigen (NSPA) protein. Elucidating the function of NSPA can then reveal CD pathogenic mechanisms and treatment opportunities. In the brain, NSPA somehow contributes to glutamatergic NMDA receptor (NMDAR) activity in synaptic plasticity and memory. Here we analyze the consequences of NSPA absence in KO mice considering its structural features shared with E3 ubiquitin ligases and the crucial role of ubiquitination in synaptic plasticity. Results Electrophysiological studies revealed a decreased long-term potentiation in CA3-CA1 and medial perforant pathway-dentate gyrus (MPP-DG) hippocampal circuits, reflecting glutamatergic synaptic plasticity impairment in NSPA-KO mice. The hippocampal dentate gyrus of these mice showed a lower number of Arc-positive cells indicative of decreased synaptic activity and also showed proliferation defects of neural progenitors underlying less adult neurogenesis. All this translates into poor spatial and recognition memory when NSPA is absent. A cell-based assay demonstrated ubiquitination of NSPA as a property of RBR-type E3 ligases, while biochemical analysis of synaptic regions disclosed the tyrosine phosphatase PTPMEG as a potential substrate. Mice lacking NSPA have increased levels of PTPMEG due to its reduced ubiquitination and proteasomal degradation, which correlated with lower levels of GluN2A and GluN2B NMDAR subunits only at postsynaptic densities (PSDs), indicating selective trafficking of these proteins out of PSDs. As both GluN2A and GluN2B interact with PTPMEG, tyrosine (Tyr) dephosphorylation likely drives their endocytic removal from the PSD. Actually, immunoblot analysis showed reduced phosphorylation of the GluN2B endocytic signal Tyr1472 in NSPA-KO mice. Conclusions NSPA contributes to hippocampal plasticity and memory processes ensuring appropriate levels of adult neurogenesis and PSD-located NMDAR. PTPMEG qualifies as NSPA ubiquitination substrate that regulates Tyr phosphorylation-dependent NMDAR stability at PSDs. The NSPA/PTPMEG pathway emerges as a new regulator of glutamatergic transmission and plasticity and may provide mechanistic clues and therapeutic opportunities for anti-P-mediated pathogenicity in SLE, a still unmet need.

Download Full-text

Effects of Adult Neurogenesis on Synaptic Plasticity in the Rat Dentate Gyrus

Journal of Neurophysiology ◽

10.1152/jn.2001.85.6.2423 ◽

2001 ◽

Vol 85 (6) ◽

pp. 2423-2431 ◽

Cited By ~ 393

Author(s):

J. S. Snyder ◽

N. Kee ◽

J. M. Wojtowicz

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Adult Neurogenesis ◽

Long Term Potentiation ◽

Receptor Blocker ◽

Granule Neurons ◽

Term Potentiation ◽

Cell Recording ◽

Similar Preparation ◽

Nmda Receptor Blocker

Ongoing neurogenesis in the adult hippocampal dentate gyrus (DG) generates a substantial population of young neurons. This phenomenon is present in all species examined thus far, including humans. Although the regulation of adult neurogenesis by various physiologically relevant factors such as learning and stress has been documented, the functional contributions of the newly born neurons to hippocampal functions are not known. We investigated possible contributions of the newly born granule neurons to synaptic plasticity in the hippocampal DG. In the standard hippocampal slice preparation perfused with artificial cerebrospinal fluid (ACSF), a small (10%) long-term potentiation (LTP) of the evoked field potentials is seen after tetanic stimulation of the afferent medial perforant pathway (MPP). The induction of this ACSF-LTP is resistant to a N-methyl-d-aspartate (NMDA) receptor blocker,d,l-2-amino-5-phosphonovaleric acid (APV), but is completely prevented by ifenprodil, a blocker of NR2B subtype of NMDA receptors. In contrast, slices perfused with picrotoxin (PICRO), a GABA-receptor blocker, revealed a larger (40–50%), APV-sensitive but ifenprodil-insensitive LTP. The ACSF-LTP required lower frequency of stimulation and fewer stimuli for its induction than the PICRO-LTP. All these characteristics of ACSF-LTP are in agreement with the properties of the putative individual new granule neurons examined previously with the use of the whole cell recording technique in a similar preparation. A causal relationship between neurogenesis and ACSF-LTP was confirmed in experiments using low dose of gamma radiation applied to the brain 3 wk prior to the electrophysiological experiments. In these experiments, the new cell proliferation was drastically reduced and ACSF-LTP was selectively blocked. We conclude that the young, adult-generated granule neurons play a significant role in synaptic plasticity in the DG. Since DG is the major source of the afferent inputs into the hippocampus, the production and the plasticity of new neurons may have an important role in the hippocampal functions such as learning and memory.

Download Full-text

Phosphorylation of the AMPAR-TARP Complex in Synaptic Plasticity

Proteomes ◽

10.3390/proteomes6040040 ◽

2018 ◽

Vol 6 (4) ◽

pp. 40 ◽

Cited By ~ 5

Author(s):

Joongkyu Park

Keyword(s):

Synaptic Plasticity ◽

Drug Addiction ◽

Ampa Receptor ◽

Long Term Potentiation ◽

Synaptic Activity ◽

Regulatory Proteins ◽

Cellular Models ◽

Brain Functions ◽

Term Potentiation

Synaptic plasticity has been considered a key mechanism underlying many brain functions including learning, memory, and drug addiction. An increase or decrease in synaptic activity of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) complex mediates the phenomena as shown in the cellular models of synaptic plasticity, long-term potentiation (LTP), and depression (LTD). In particular, protein phosphorylation shares the spotlight in expressing the synaptic plasticity. This review summarizes the studies on phosphorylation of the AMPAR pore-forming subunits and auxiliary proteins including transmembrane AMPA receptor regulatory proteins (TARPs) and discusses its role in synaptic plasticity.

Download Full-text

Levetiracetam Reduced the Basal Excitability of the Dentate Gyrus without Restoring Impaired Synaptic Plasticity in Rats with Temporal Lobe Epilepsy

Brain Sciences ◽

10.3390/brainsci10090634 ◽

2020 ◽

Vol 10 (9) ◽

pp. 634

Author(s):

Guillermo González-H ◽

Itzel Jatziri Contreras-García ◽

Karla Sánchez-Huerta ◽

Claudio M. T. Queiroz ◽

Luis Ricardo Gallardo Gudiño ◽

...

Keyword(s):

Synaptic Plasticity ◽

Temporal Lobe Epilepsy ◽

Dentate Gyrus ◽

Temporal Lobe ◽

Focal Epilepsy ◽

Chronic Phase ◽

Long Term Potentiation ◽

Excitatory Postsynaptic Potential ◽

Output Curve

Temporal lobe epilepsy (TLE), the most common type of focal epilepsy, affects learning and memory; these effects are thought to emerge from changes in synaptic plasticity. Levetiracetam (LEV) is a widely used antiepileptic drug that is also associated with the reversal of cognitive dysfunction. The long-lasting effect of LEV treatment and its participation in synaptic plasticity have not been explored in early chronic epilepsy. Therefore, through the measurement of evoked field potentials, this study aimed to comprehensively identify the alterations in the excitability and the short-term (depression/facilitation) and long-term synaptic plasticity (long-term potentiation, LTP) of the dentate gyrus of the hippocampus in a lithium–pilocarpine rat model of TLE, as well as their possible restoration by LEV (1 week; 300 mg/kg/day). TLE increased the population spike (PS) amplitude (input/output curve); interestingly, LEV treatment partially reduced this hyperexcitability. Furthermore, TLE augmented synaptic depression, suppressed paired-pulse facilitation, and reduced PS-LTP; however, LEV did not alleviate such alterations. Conversely, the excitatory postsynaptic potential (EPSP)-LTP of TLE rats was comparable to that of control rats and was decreased by LEV. LEV caused a long-lasting attenuation of basal hyperexcitability but did not restore impaired synaptic plasticity in the early chronic phase of TLE.

Download Full-text

Inhibition of PI3K-Akt Signaling Blocks Exercise-Mediated Enhancement of Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

PLoS ONE ◽

10.1371/journal.pone.0007901 ◽

2009 ◽

Vol 4 (11) ◽

pp. e7901 ◽

Cited By ~ 83

Author(s):

Elodie Bruel-Jungerman ◽

Alexandra Veyrac ◽

Franck Dufour ◽

Jennifer Horwood ◽

Serge Laroche ◽

...

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Adult Neurogenesis ◽

Akt Signaling

Download Full-text

Emerging Link between Alzheimer’s Disease and Homeostatic Synaptic Plasticity

Neural Plasticity ◽

10.1155/2016/7969272 ◽

2016 ◽

Vol 2016 ◽

pp. 1-19 ◽

Cited By ~ 29

Author(s):

Sung-Soo Jang ◽

Hee Jung Chung

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Synaptic Plasticity ◽

Senile Plaques ◽

Long Term Potentiation ◽

Brain Regions ◽

Synaptic Activity ◽

Homeostatic Plasticity ◽

Brain Disorder

Alzheimer’s disease (AD) is an irreversible brain disorder characterized by progressive cognitive decline and neurodegeneration of brain regions that are crucial for learning and memory. Although intracellular neurofibrillary tangles and extracellular senile plaques, composed of insoluble amyloid-β(Aβ) peptides, have been the hallmarks of postmortem AD brains, memory impairment in early AD correlates better with pathological accumulation of soluble Aβoligomers and persistent weakening of excitatory synaptic strength, which is demonstrated by inhibition of long-term potentiation, enhancement of long-term depression, and loss of synapses. However, current, approved interventions aiming to reduce Aβlevels have failed to retard disease progression; this has led to a pressing need to identify and target alternative pathogenic mechanisms of AD. Recently, it has been suggested that the disruption of Hebbian synaptic plasticity in AD is due to aberrant metaplasticity, which is a form of homeostatic plasticity that tunes the magnitude and direction of future synaptic plasticity based on previous neuronal or synaptic activity. This review examines emerging evidence for aberrant metaplasticity in AD. Putative mechanisms underlying aberrant metaplasticity in AD will also be discussed. We hope this review inspires future studies to test the extent to which these mechanisms contribute to the etiology of AD and offer therapeutic targets.

Download Full-text

Long-term potentiation expands information content of hippocampal dentate gyrus synapses

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1716189115 ◽

2018 ◽

Vol 115 (10) ◽

pp. E2410-E2418 ◽

Cited By ~ 19

Author(s):

Cailey Bromer ◽

Thomas M. Bartol ◽

Jared B. Bowden ◽

Dusten D. Hubbard ◽

Dakota C. Hanka ◽

...

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Storage Capacity ◽

Unit Length ◽

Long Term Potentiation ◽

Information Storage ◽

Perforant Path ◽

Hippocampal Dentate Gyrus ◽

Term Potentiation

An approach combining signal detection theory and precise 3D reconstructions from serial section electron microscopy (3DEM) was used to investigate synaptic plasticity and information storage capacity at medial perforant path synapses in adult hippocampal dentate gyrus in vivo. Induction of long-term potentiation (LTP) markedly increased the frequencies of both small and large spines measured 30 minutes later. This bidirectional expansion resulted in heterosynaptic counterbalancing of total synaptic area per unit length of granule cell dendrite. Control hemispheres exhibited 6.5 distinct spine sizes for 2.7 bits of storage capacity while LTP resulted in 12.9 distinct spine sizes (3.7 bits). In contrast, control hippocampal CA1 synapses exhibited 4.7 bits with much greater synaptic precision than either control or potentiated dentate gyrus synapses. Thus, synaptic plasticity altered total capacity, yet hippocampal subregions differed dramatically in their synaptic information storage capacity, reflecting their diverse functions and activation histories.

Download Full-text

Reduced Synaptic Plasticity in the Lateral Perforant Path Input to the Dentate Gyrus of Aged C57BL/6 Mice

Journal of Neurophysiology ◽

10.1152/jn.00105.2003 ◽

2003 ◽

Vol 90 (1) ◽

pp. 32-38 ◽

Cited By ~ 23

Author(s):

David J. Froc ◽

Brennan Eadie ◽

Amanda M. Li ◽

Karl Wodtke ◽

Maric Tse ◽

...

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Hippocampal Slices ◽

Long Term Potentiation ◽

Significant Degree ◽

Perforant Path ◽

High Frequency Stimulation ◽

Synaptic Efficacy ◽

Term Potentiation ◽

Effects Of Aging

Hippocampal slices obtained from C57BL/6 mice (3–25 mo) were used to investigate the effects of aging on excitatory postsynaptic potentials (EPSPs) elicited in dentate gyrus with lateral perforant path stimulation. The maximal amplitude of the EPSP, as well as the degree of paired-pulse facilitation, was significantly reduced in animals aged 12 mo or more compared with younger animals (<12 mo). Although all animals showed equivalent short-term potentiation (STP) in response to high-frequency stimulation, this did not translate into a long-lasting increase in synaptic efficacy in the older animals. A significant degree of long-term potentiation (LTP) of synaptic efficacy was only observed in animals <12 mo of age when measured 30 min after induction. Blocking GABAA-mediated inhibition significantly enhanced STP in younger and older animals; however, a significant degree of LTP was again only observed in slices taken from younger animals. These data indicate that the lateral perforant path input to the dentate gyrus is altered by the aging process, and that this results in a reduction in the capacity of this input to exhibit long-lasting synaptic plasticity.

Download Full-text

Medial amygdala enhances synaptic transmission and synaptic plasticity in the dentate gyrus of rats in vivo

Journal of Neurophysiology ◽

10.1152/jn.1995.74.5.2201 ◽

1995 ◽

Vol 74 (5) ◽

pp. 2201-2203 ◽

Cited By ~ 22

Author(s):

Y. Ikegaya ◽

K. Abe ◽

H. Saito ◽

N. Nishiyama

Keyword(s):

Synaptic Plasticity ◽

Synaptic Transmission ◽

Dentate Gyrus ◽

High Frequency ◽

Long Term Potentiation ◽

Perforant Path ◽

High Frequency Stimulation ◽

Medial Amygdala ◽

Frequency Stimulation ◽

Stimulation Of

1. The present experiment was designed to test whether synaptic transmission and synaptic plasticity in the dentate gyrus were modulated by the medial amygdala (MeA). Field potentials in the dentate gyrus (DG) evoked by stimulations of the medial perforant path (PP) were extracellularly recorded in anesthetized rats. 2. Although single-pulse stimulation of the MeA augmented PP stimulation-evoked population spike amplitude in the DG transiently, high-frequency stimulation (100 Hz for 1 s) of the MeA induced long-lasting enhancement of synaptic transmission that was not occluded by PP tetanus-induced long-term potentiation (LTP). 3. When high-frequency stimulation of the MeA was applied concurrently with weak tetanus of the PP, which alone induced only marginal LTP, the magnitude of LTP increased considerably. 4. These results demonstrate that neuron activities in the MeA induce short- and long-lasting changes in the excitability of the PP-DG synapses and thereby enhance their synaptic plasticity.

Download Full-text

Intermittent Hypoxia Disrupts Adult Neurogenesis and Synaptic Plasticity in the Dentate Gyrus

Journal of Neuroscience ◽

10.1523/jneurosci.1359-18.2018 ◽

2018 ◽

Vol 39 (7) ◽

pp. 1320-1331 ◽

Cited By ~ 9

Author(s):

Maggie A. Khuu ◽

Chelsea M. Pagan ◽

Thara Nallamothu ◽

Robert F. Hevner ◽

Rebecca D. Hodge ◽

...

Keyword(s):

Synaptic Plasticity ◽

Dentate Gyrus ◽

Adult Neurogenesis ◽

Intermittent Hypoxia

Download Full-text

Syndapin I Loss-of-Function in Mice Leads to Schizophrenia-Like Symptoms

Cerebral Cortex ◽

10.1093/cercor/bhaa013 ◽

2020 ◽

Vol 30 (8) ◽

pp. 4306-4324 ◽

Cited By ~ 1

Author(s):

Nicole Koch ◽

Dennis Koch ◽

Sarah Krueger ◽

Jessica Tröger ◽

Victor Sabanov ◽

...

Keyword(s):

Synaptic Plasticity ◽

Long Term Potentiation ◽

Synaptic Activity ◽

Actin Dynamics ◽

Loss Of Function ◽

Cellular Mechanisms ◽

Long Term Depression ◽

Membrane Recruitment ◽

Term Potentiation

Abstract Schizophrenia is associated with cognitive and behavioral dysfunctions thought to reflect imbalances in neurotransmission systems. Recent screenings suggested that lack of (functional) syndapin I (PACSIN1) may be linked to schizophrenia. We therefore studied syndapin I KO mice to address the suggested causal relationship to schizophrenia and to analyze associated molecular, cellular, and neurophysiological defects. Syndapin I knockout (KO) mice developed schizophrenia-related behaviors, such as hyperactivity, reduced anxiety, reduced response to social novelty, and an exaggerated novel object response and exhibited defects in dendritic arborization in the cortex. Neuromorphogenic deficits were also observed for a schizophrenia-associated syndapin I mutant in cultured neurons and coincided with a lack of syndapin I–mediated membrane recruitment of cytoskeletal effectors. Syndapin I KO furthermore caused glutamatergic hypofunctions. Syndapin I regulated both AMPAR and NMDAR availabilities at synapses during basal synaptic activity and during synaptic plasticity—particularly striking were a complete lack of long-term potentiation and defects in long-term depression in syndapin I KO mice. These synaptic plasticity defects coincided with alterations of postsynaptic actin dynamics, synaptic GluA1 clustering, and GluA1 mobility. Both GluA1 and GluA2 were not appropriately internalized. Summarized, syndapin I KO led to schizophrenia-like behavior, and our analyses uncovered associated molecular and cellular mechanisms.

Download Full-text