In:
Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 108, No. 35 ( 2011-08-30)
Abstract:
Together, our findings suggest an unusual mechanism by which selected neurons are integrated into a coherent pattern of network activity. The resulting well-defined neuronal assemblies may constitute a correlate of memories at the network level, thus bridging the critical gap between single-cell mechanisms of synaptic plasticity and system-level learning. Our data reveal a mechanism by which neurons are recruited into assemblies: spike generation in axonal compartments that is largely independent of dendritic synaptic inputs. GABAergic inhibition plays a dual role in assembly formation. First, perisomatic inhibition ensures sparse firing and strict separation between participating and nonparticipating neurons. Second, GABA-mediated enhancement of axonal excitability facilitates ectopic spike generation. In this way, SPW-R–associated assemblies are linked to local inhibitory activity and hence, conventional synaptic network mechanisms. In addition, antidromic spikes may propagate into the dendrites where they can interact with synaptic excitation and support synaptic plasticity. To put our results into a network context, we constructed a detailed computer model of the hippocampal subregion CA1, extending previous work ( 4 ). We suggest the following mechanism: During SPW-Rs, action potentials arise within fine axon collaterals, probably facilitated by GABA release from strongly activated interneurons. Spikes propagate to the main axon, but they are frequently aborted at branching points. Some spikes survive and invade the soma antidromically (i.e., against the usual direction of spike propagation). In our somatic recordings, these action potentials appear with the peculiar waveform of antidromic spikes. In the model, the ripple network oscillation arises from electrical coupling between axons, consistent with previous work ( 4 ). According to our hypothesis, participating neurons are distinguished by expressing interaxonal gap junctions. The underlying molecular and morphological specializations need to be identified in more experiments that also take into account different suggested mechanisms for fast oscillatory network activity ( 5 ). Inhibitory interneurons are considered key elements in the temporal and spatial organization of network activity. In our recordings, this finding was visible from the hyperpolarizing (negative) potential preceding network-coupled action potentials, which are typical of inhibitory synaptic transmission. We analyzed the role of inhibition in some detail by recording from inhibitory interneurons and found that they were indeed heavily activated during SPW-R. The resulting strong inhibition of pyramidal cells may enhance signal to noise ratio by suppressing any background activity of nonparticipating neurons. At the remote axonal compartment where the SPW-R–coupled spikes were generated, GABA had opposite effects —it facilitated rather than suppressed generation of the antidromic action potentials ( 3 ). We performed extracellular recordings of SPW-R, which reflect summed dendritic excitatory postsynaptic currents and perisomatic inhibitory currents at ∼200 Hz (ripple oscillation riding on top of the sharp wave) ( 1 ). In addition, we attempted to determine how individual cells are entrained by the local network. Of 153 recorded CA1 pyramidal cells, 41% fired occasionally during SPW-Rs ( Fig. P1 B ). Surprisingly, the remaining cells (∼59%) never participated in SPW-Rs, even on strong depolarization. Thus, participating and nonparticipating cells are clearly distinct during SPW-Rs. In addition, we found evidence suggesting that spikes were being generated within remote compartments of the axon without prior depolarization ( Fig. P1 C ) ( 2 ). Indeed, such action potentials evoked by electrical stimulation of axons or application of 4-aminopyridine into the axonal bundle (called alveus) had the same characteristics ( Fig. P1 D ). How does the vast number of neurons in the brain enable highly reproducible actions such as coordinated movements, correct perception of relevant object features, or reliable memories? It has been suggested that neuronal networks include groups of highly interconnected neurons, which, on partial activation, recruit each other into stable activity patterns. Such neuronal assemblies may form the neuronal basis of memories. It is, however, unknown how neurons know whether they are part of a given assembly. We have studied this question in a model of sharp wave-ripple complexes (SPW-Rs), a well-delineated pattern of network activity in the mammalian hippocampal formation ( Fig. P1 A and B ), which is a brain region implicated in learning and memory. SPW-Rs involve the activation of preselected neurons and may contribute to memory consolidation. We used an in vitro model of SPW-Rs in a mouse brain slice preparation to search for differences between participating and nonparticipating neurons. In accordance with the concept of stable neuronal assemblies, SPW-R–coupled action potentials were exclusively observed in a distinct subgroup of pyramidal neurons (cells that transfer information to upstream brain centers). Unique properties distinguished these spikes from action potentials outside SPW-R. Normally, action potentials are generated at the initial segment of the axon, with the potential emanating from the cell body (soma) and passing onto all target cells of the neuron. The positive voltage deflection triggering such action potentials is normally generated in dendrites, another type of neuronal structure that receives synaptic input from different neurons. In short, the dendrites work as antennas, and the axons work as output cables. In contrast, action potentials coupled to the network oscillation pattern of SPW-R were generated at remote sites within the axon. Subsequently, they invaded the cell body and the dendrites against the normal direction of signal propagation or antidromically. During SPW-Rs, there was intense release of the inhibitory neurotransmitter GABA from local interneurons. This release led to a complete suppression of normal action potentials (spikes that are generated in the initial segment of the axon after dendritic excitation). In distal axonal compartments, however, GABA facilitated the generation of action potentials during SPW-Rs, underlining the unique properties of these spikes. Together, these findings provide a mechanism by which selected neurons are recruited into neuronal assemblies.
Type of Medium:
Online Resource
ISSN:
0027-8424
,
1091-6490
DOI:
10.1073/pnas.1103546108
Language:
English
Publisher:
Proceedings of the National Academy of Sciences
Publication Date:
2011
detail.hit.zdb_id:
209104-5
detail.hit.zdb_id:
1461794-8
SSG:
11
SSG:
12
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