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Synaptic Plasticity by Antidromic Firing During Hippocampal Network

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Synaptic Plasticity by Antidromic Firing During Hippocampal Network Synaptic plasticity by antidromic firing during hippocampal network oscillations Olena Bukaloa, Emilie Campanacb, Dax A. Hoffmanb, and R. Douglas Fieldsa,1 aNervous System Development and Plasticity Section, and bMolecular Neurophysiology and Biophysics Section, Program in Development Neuroscience, The Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892 Edited* by Nancy J. Kopell, Boston University, Boston, MA, and approved February 11, 2013 (received for review June 25, 2012) Learning and other cognitive tasks require integrating new expe- is firing of antidromic action potentials generated spontaneously riences into context. In contrast to sensory-evoked synaptic plas- in the distal region of axons in a nonclassical mode (ectopically) ticity, comparatively little is known of how synaptic plasticity may (11, 12). Ectopic spike generation is facilitated by GABA- be regulated by intrinsic activity in the brain, much of which can mediated axonal depolarization and electrotonic coupling through involve nonclassical modes of neuronal firing and integration. axonal gap junctions (11, 13). Since ectopic action potentials may Coherent high-frequency oscillations of electrical activity in CA1 propagate antidromically into the dendritic field of CA1 neurons hippocampal neurons [sharp-wave ripple complexes (SPW-Rs)] (14), synaptic strength may be altered in all synaptic inputs to functionally couple neurons into transient ensembles. These oscil- neurons participating in SPW-Rs. lations occur during slow-wave sleep or at rest. Neurons that It is thought that synaptic down-scaling during SWS is neces- participate in SPW-Rs are distinguished from adjacent nonpartici- sary to prevent saturation of synapses that become potentiated pating neurons by firing action potentials that are initiated during wakefulness (15), and assimilation of new memories into ectopically in the distal region of axons and propagate antidrom- a schema by an increase of the signal-to-noise ratio and re- ically to the cell body. This activity is facilitated by GABAA-mediated finement and sharpening of previously acquired memories (3). depolarization of axons and electrotonic coupling. The possible There are some data in support of synaptic rescaling during effects of antidromic firing on synaptic strength are unknown. SWS, including decreased amplitude of evoked responses (16– We find that facilitation of spontaneous SPW-Rs in hippocampal 18) and reduced spontaneous activity (19, 20). We sought to slices by increasing gap-junction coupling or by GABAA-mediated determine whether SPW-Rs induce downscaling of synaptic NEUROSCIENCE axon depolarization resulted in a reduction of synaptic strength, strength and if so to identify the mechanism. Specifically, the and electrical stimulation of axons evoked a widespread, long-lasting causal relation that we are investigating is between the anti- synaptic depression. Unlike other forms of synaptic plasticity, this dromic firing and changes in synaptic strength, not strictly synaptic depression is not dependent upon synaptic input or gluta- a possible relation between the SPW-Rs and synaptic strength as mate receptor activation, but rather requires L-type calcium chan- network oscillations will have multiple effects. Our findings nel activation and functional gap junctions. Synaptic stimulation bridge between current literature seeking to understand how fi delivered after antidromic ring, which was otherwise too weak SPW-Rs are involved in mediating memory consolidation by to induce synaptic potentiation, triggered a long-lasting increase in identifying the cellular mechanisms (antidromic firing) for this synaptic strength. Rescaling synaptic weights in subsets of neu- fi fi new form of synaptic depression. Our data con rm this hy- rons ring antidromically during SPW-Rs might contribute to pothesis and reveal a unique form of cell-wide synaptic plasticity memory consolidation by sharpening specificity of subsequent that is initiated by antidromic action potentials. synaptic input and promoting incorporation of novel information. Results long-term depression | long-term potentiation | network plasticity | Facilitation of Spontaneous SPW-Rs Leads to Reduction in Synaptic excitability Strength. Spontaneous SPW-Rs can be recorded in acute hip- pocampal slice preparations (21). We tested whether increasing emory requires more than recording sensory input (1–3). the occurrence of SPW-Rs, and associated antidromic action MNew sensory experience must be incorporated into a cog- potential firing (11), would result in changes in synaptic strength nitive framework, or schema, that preserves temporal sequence in the hippocampal CA1 region. It has been demonstrated that and associates the new information together with other relevant GABAA receptor activation, which depolarizes axons and hy- aspects of the experience (4). This central processing requires perpolarizes somatodentritic regions, facilitates antidromic spike coupling neurons into transiently stable functional assemblies generation in CA1 neurons during SPW-Rs (11, 12). Our studies and transferring information between different brain regions (2, show that local injection of muscimol, a GABAA receptor ago- 5). The functional coupling of neurons within assemblies is be- nist, to axons in the alveus evoked depression of synaptic re- lieved to be organized by network oscillations that cover multiple sponses, which lasted for 90 min after muscimol withdrawal frequency bands and follow distinct mechanisms (6). During (Fig. S1A). Although GABA-mediated depolarization of axons, slow-wave sleep (SWS) and quiet wakefulness, characterized by associated with antidromic firing during SPW-Rs, is sufficient decreased sensory and cognitive processing, hippocampal neu- to induce transient depression of synaptic response in the CA1 rons fire in brief periods of high-frequency coherent oscillations region, activation of additional mechanisms may be required to (100–300 Hz), termed sharp-wave ripple complexes (SPW-Rs). SPW-Rs coincide with periods of offline replay of neural sequences learned during encoding sensory information (7, 8). Disrupting Author contributions: O.B., D.A.H., and R.D.F. designed research; O.B. and E.C. performed SPW-Rs, and therefore replay, impairs memory retention (9, 10), research; O.B., E.C., and R.D.F. analyzed data; and O.B. and R.D.F. wrote the paper. suggesting that replay of activity sequences during resting states is The authors declare no conflict of interest. critical for memory consolidation. However, little is known of how *This Direct Submission article had a prearranged editor. synaptic strength may be affected by SPW-Rs’ that are associ- Freely available online through the PNAS open access option. ated with memory consolidation in the hippocampus. 1To whom correspondence should be addressed. E-mail: fi[email protected]. Recent studies demonstrate that a distinguishing feature of This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. individual CA1 hippocampal neurons that participate in SPW-Rs 1073/pnas.1210735110/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1210735110 PNAS Early Edition | 1of6 Downloaded by guest on September 28, 2021 Antidromic Stimulation of Axons Induces LTD. To determine whether LTD that develops after increasing SPW-Rs is medi- ated by synchronous antidromic action potential firing, we applied electrical stimulation to axons in the alveus to induce antidromic firing in CA1 neurons directly. Repeated theta-burst stimulation (TBS) delivered antidromically to axons evoked AP-LTD [LTD induced by antidromic action potentials (APs)] in CA1 stratum radiatum (Fig. 2A). When antidromic stimulation (AS) was delivered in the presence of glutamatergic antagonists, AP-LTD was not blocked (Fig. 2B), indicating that excitatory synaptic A AS OS Fig. 1. Facilitation of spontaneous SPW-Rs leads to reduction in synaptic strength. (A) Representative field potential recording of spontaneous SPW- AS Rs recorded in stratum pyramidale of area CA1 (Top). Opening gap junctions B with NH4Cl (10 mM) added to perfusate in the presence of glutamatergic antagonists kynurenic acid (3 mM), DL-2-Amino-5-phosphonopentanoic acid (APV) (50 μM), and (RS)-α-Methyl-4-carboxyphenylglycine (MCPG) (250 μM) increased the number and duration of spontaneous SPW-Rs in CA1 (Middle), which is prevented by gap-junction blocker carbenoxolone (100 μM) (Bottom). Corresponding expanded events are shown on the right. (B) LTD can be induced by NH4Cl in the presence of glutamatergic antago- nists (dashed vertical bar) (53.8 ± 7.2%, P < 0.05) and is blocked by addition of carbenoxolone (92.5 ± 9.1%, P < 0.01). Carbenoxolone and NH4Cl appli- cation is indicated by horizontal bar. Representative synaptic responses evoked and recorded in the stratum radiatum before (black) and after (gray) treatment are shown on the right. AS transform this depression to a long-lasting change. Alternatively, activation of nonaxonal GABAA receptors by muscimol could C result in hyperpolarizing response (22, 23), and thus limit axonal depolarization and action potential propagation. We therefore tested the effect of increasing SPW-Rs using a different method. Electrotonic coupling through gap junc- tions located between axons of hippocampal projection cells are crucial for very fast oscillations, including neuronal syn- chronization during SPW-Rs (13, 21, 24). SPW-R frequency increased 3.8 times when gap junctions were
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