Synaptic plasticity and cognitive function are disrupted in the absence of Lrp4

Lrp4, the muscle receptor for neuronal Agrin, is expressed in the hippocampus and areas involved in cognition. The function of Lrp4 in the brain, however, is unknown, as Lrp4−/− mice fail to form neuromuscular synapses and die at birth. Lrp4−/− mice, rescued for Lrp4 expression selectively in muscle, survive into adulthood and showed profound deficits in cognitive tasks that assess learning and memory. To learn whether synapses form and function aberrantly, we used electrophysiological and anatomical methods to study hippocampal CA3–CA1 synapses. In the absence of Lrp4, the organization of the hippocampus appeared normal, but the frequency of spontaneous release events and spine density on primary apical dendrites were reduced. CA3 input was unable to adequately depolarize CA1 neurons to induce long-term potentiation. Our studies demonstrate a role for Lrp4 in hippocampal function and suggest that patients with mutations in Lrp4 or auto-antibodies to Lrp4 should be evaluated for neurological deficits.

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Ultrastructure of light-activated axons following optogenetic stimulation to produce late-phase long-term potentiation

10.1101/799890 ◽

2019 ◽

Author(s):

Masaaki Kuwajima ◽

Olga I. Ostrovskaya ◽

Guan Cao ◽

Seth A. Weisberg ◽

Kristen M. Harris ◽

...

Keyword(s):

Late Phase ◽

Long Term Potentiation ◽

State Dependent ◽

Term Potentiation ◽

Section Electron ◽

Hippocampal Ca3 ◽

Ultrastructure And Function ◽

Ca3 Neurons ◽

And Function

AbstractAnalysis of neuronal compartments has revealed many state-dependent changes in geometry but establishing synapse-specific mechanisms at the nanoscale has proven elusive. We co-expressed channelrhodopsin2-GFP and mAPEX2 in a subset of hippocampal CA3 neurons and used trains of light to induce late-phase long-term potentiation (L-LTP) in area CA1. L-LTP was shown to be specific to the labeled axons by severing CA3 inputs, which prevented back-propagating recruitment of unlabeled axons. Membrane-associated mAPEX2 tolerated microwave-enhanced chemical fixation and drove tyramide signal amplification to deposit Alexa Fluor dyes in the light-activated axons. Subsequent post-embedding immunogold labeling resulted in outstanding ultrastructure and clear distinctions between labeled (activated), and unlabeled axons without obscuring subcellular organelles. The gold-labeled axons in potentiated slices were reconstructed through serial section electron microscopy; presynaptic vesicles and other constituents could be quantified unambiguously. The genetic specification, reliable physiology, and compatibility with established methods for ultrastructural preservation make this an ideal approach to link synapse ultrastructure and function in intact circuits.

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Properties of subsequent induction of long-term potentiation and/or depression in one synaptic input in apical dendrites of hippocampal CA1 neurons in vitro

Neuroscience ◽

10.1016/j.neuroscience.2010.09.018 ◽

2010 ◽

Vol 171 (3) ◽

pp. 712-720 ◽

Cited By ~ 3

Author(s):

S. Parvez ◽

B. Ramachandran ◽

J.U. Frey

Keyword(s):

Synaptic Input ◽

Long Term Potentiation ◽

Ca1 Neurons ◽

Hippocampal Ca1 Neurons ◽

Term Potentiation ◽

Hippocampal Ca1 ◽

Apical Dendrites

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Photolysis of Postsynaptic Caged Ca2+ Can Potentiate and Depress Mossy Fiber Synaptic Responses in Rat Hippocampal CA3 Pyramidal Neurons

Journal of Neurophysiology ◽

10.1152/jn.01073.2003 ◽

2004 ◽

Vol 91 (4) ◽

pp. 1596-1607 ◽

Cited By ~ 17

Author(s):

Jun Wang ◽

Mark F. Yeckel ◽

Daniel Johnston ◽

Robert S. Zucker

Keyword(s):

Tyrosine Kinases ◽

Pyramidal Neurons ◽

Mossy Fiber ◽

Long Term Potentiation ◽

Ca1 Neurons ◽

Term Potentiation ◽

Hippocampal Ca3 ◽

Ca3 Pyramidal Neurons ◽

Cell Somata

The induction of mossy fiber-CA3 long-term potentiation (LTP) and depression (LTD) has been variously described as being dependent on either pre- or postsynaptic factors. Some of the postsynaptic factors for LTP induction include ephrin-B receptor tyrosine kinases and a rise in postsynaptic Ca2+ ([Ca2+]i). Ca2+ is also believed to be involved in the induction of the various forms of LTD at this synapse. We used photolysis of caged Ca2+ compounds to test whether a postsynaptic rise in [Ca2+]i is sufficient to induce changes in synaptic transmission at mossy fiber synapses onto rat hippocampal CA3 pyramidal neurons. We were able to elevate postsynaptic [Ca2+]i to approximately 1 μm for a few seconds in pyramidal cell somata and dendrites. We estimate that CA3 pyramidal neurons have approximately fivefold greater endogenous Ca2+ buffer capacity than CA1 neurons, limiting the rise in [Ca2+]i achievable by photolysis. This [Ca2+]i rise induced either a potentiation or a depression at mossy fiber synapses in different preparations. Neither the potentiation nor the depression was accompanied by consistent changes in paired-pulse facilitation, suggesting that these forms of plasticity may be distinct from synaptically induced LTP and LTD at this synapse. Our results are consistent with a postsynaptic locus for the induction of at least some forms of synaptic plasticity at mossy fiber synapses.

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Acute cocaine exposure alters spine density and long-term potentiation in the ventral tegmental area

European Journal of Neuroscience ◽

10.1111/j.1460-9568.2007.05689.x ◽

2007 ◽

Vol 26 (3) ◽

pp. 749-756 ◽

Cited By ~ 60

Author(s):

Federica Sarti ◽

Stephanie L. Borgland ◽

Viktor N. Kharazia ◽

Antonello Bonci

Keyword(s):

Ventral Tegmental Area ◽

Long Term Potentiation ◽

Spine Density ◽

Cocaine Exposure ◽

Term Potentiation ◽

Ventral Tegmental

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AMPA Silencing Is a Prerequisite for Developmental Long-Term Potentiation in the Hippocampal CA1 Region

Journal of Neurophysiology ◽

10.1152/jn.90476.2008 ◽

2008 ◽

Vol 100 (5) ◽

pp. 2605-2614 ◽

Cited By ~ 23

Author(s):

Therése Abrahamsson ◽

Bengt Gustafsson ◽

Eric Hanse

Keyword(s):

Developmental Stages ◽

Long Term Potentiation ◽

Synaptic Strength ◽

Ca1 Region ◽

Hippocampal Ca1 Region ◽

Silent Synapses ◽

Term Potentiation ◽

Hippocampal Ca1 ◽

Hippocampal Ca3

AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) unsilencing is an often proposed expression mechanism both for developmental long-term potentiation (LTP), involved in circuitry refinement during brain development, and for mature LTP, involved in learning and memory. In the hippocampal CA3–CA1 connection naïve (nonstimulated) synapses are AMPA signaling and AMPA-silent synapses are created from naïve AMPA-signaling (AMPA-labile) synapses by test-pulse synaptic activation (AMPA silencing). To investigate to what extent LTPs at different developmental stages are explained by AMPA unsilencing, the amount of LTP obtained at these different developmental stages was related to the amount of AMPA silencing that preceded the induction of LTP. When examined in the second postnatal week Hebbian induction was found to produce no more stable potentiation than that causing a return to the naïve synaptic strength existing prior to the AMPA silencing. Moreover, in the absence of a preceding AMPA silencing Hebbian induction produced no stable potentiation above the naïve synaptic strength. Thus this early, or developmental, LTP is nothing more than an unsilencing (dedepression) and stabilization of the AMPA signaling that was lost by the prior AMPA silencing. This dedepression and stabilization of AMPA signaling was mimicked by the presence of the protein kinase A activator forskolin. As the relative degree of AMPA silencing decreased with development, LTP manifested itself more and more as a “genuine” potentiation (as opposed to a dedepression) not explained by unsilencing and stabilization of AMPA-labile synapses. This “genuine,” or mature, LTP rose from close to nothing of total LTP prior to postnatal day (P)13, to about 70% of total LTP at P16, and to about 90% of total LTP at P30. Developmental LTP, by stabilization of AMPA-labile synapses, thus seems adapted to select synaptic connections to the growing synaptic network. Mature LTP, by instead strengthening existing stable connections between cells, may then create functionally tightly connected cell assemblies within this network.

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