Cellular correlate of assembly formation in oscillating hippocampal networks in vitro

Abstract

Neurons form transiently stable assemblies that may underlie cognitive functions, including memory formation. In most brain regions, coherent activity is organized by network oscillations that involve sparse firing within a well-defined minority of cells. Despite extensive work on the underlying cellular mechanisms, a fundamental question remains unsolved: how are participating neurons distinguished from the majority of nonparticipators? We used physiological and modeling techniques to analyze neuronal activity in mouse hippocampal slices during spontaneously occurring high-frequency network oscillations. Network-entrained action potentials were exclusively observed in a defined subset of pyramidal cells, yielding a strict distinction between participating and nonparticipating neurons. These spikes had unique properties, because they were generated in the axon without prior depolarization of the soma. GABA A receptors had a dual role in pyramidal cell recruitment. First, the sparse occurrence of entrained spikes was accomplished by intense perisomatic inhibition. Second, antidromic spike generation was facilitated by tonic effects of GABA in remote axonal compartments. Ectopic spike generation together with strong somatodendritic inhibition may provide a cellular mechanism for the definition of oscillating assemblies.antidromic action potentials | CA1 pyramidal cells | interneurons | ripples I nformation processing in neuronal networks has been proposed to rely on coordinated patterns of activity in transiently stable neuronal assemblies (1). Such patterns underlie different cognitive or behavioral tasks including motor patterns (2), perception (3), and spatial cognition (4). The functional coupling of neurons within distributed assemblies is believed to be organized by network oscillations that cover multiple frequency bands and follow distinct mechanisms (5). However, it is still unclear how neurons within an activated assembly are distinguished from the majority of nonparticipating cells. This distinction is essential for maintaining sparse and stable neural representations (6).Spatial memory formation in rodents has become an important model system for studying neuronal representations within networks. Place-selective neurons of the hippocampus are sequentially activated during exploration of an environment and reactivated during subsequent resting periods (7), indicating the formation of stable assemblies. During reactivation, temporal and spatial precision of pyramidal cell firing is organized by propagating sharp waves with superimposed high-frequency network oscillations [sharp wave ripple complexes (SPW-Rs)] (8, 9). While traveling through the CA1 area, each SPW-R recruits only a few selected cells to fire action potentials (8), whereas the majority of nonparticipating cells is silent, ensuring clear signal to noise separation (10). The mechanisms underlying this functional distinction between participating and nonparticipating cells are, however, unclear. Recordings in vivo (11) and in vitro (12) have ...

Synaptic plasticity by antidromic firing during hippocampal network oscillations

“…We tested whether increasing the occurrence of SPW-Rs, and associated antidromic action potential firing (11), would result in changes in synaptic strength in the hippocampal CA1 region. It has been demonstrated that GABA A receptor activation, which depolarizes axons and hyperpolarizes somatodentritic regions, facilitates antidromic spike generation in CA1 neurons during SPW-Rs (11,12). Our studies show that local injection of muscimol, a GABA A receptor agonist, to axons in the alveus evoked depression of synaptic responses, which lasted for 90 min after muscimol withdrawal (Fig.…”

“…Disrupting SPW-Rs, and therefore replay, impairs memory retention (9, 10), suggesting that replay of activity sequences during resting states is critical for memory consolidation. However, little is known of how synaptic strength may be affected by SPW-Rs' that are associated with memory consolidation in the hippocampus.Recent studies demonstrate that a distinguishing feature of individual CA1 hippocampal neurons that participate in SPW-Rs is firing of antidromic action potentials generated spontaneously in the distal region of axons in a nonclassical mode (ectopically) (11,12). Ectopic spike generation is facilitated by GABAmediated axonal depolarization and electrotonic coupling through axonal gap junctions (11, 13).…”

“…Recent studies demonstrate that a distinguishing feature of individual CA1 hippocampal neurons that participate in SPW-Rs is firing of antidromic action potentials generated spontaneously in the distal region of axons in a nonclassical mode (ectopically) (11,12). Ectopic spike generation is facilitated by GABAmediated axonal depolarization and electrotonic coupling through axonal gap junctions (11,13).…”

“…Ectopic spike generation is facilitated by GABAmediated axonal depolarization and electrotonic coupling through axonal gap junctions (11,13). Since ectopic action potentials may propagate antidromically into the dendritic field of CA1 neurons (14), synaptic strength may be altered in all synaptic inputs to neurons participating in SPW-Rs.…”

Highly Energized Inhibitory Interneurons are a Central Element for Information Processing in Cortical Networks

“…During fast network oscillations, almost all local neurons are phasically inhibited on every oscillation cycle, and most of this inhibition is perisomatic, i.e., at the soma, the proximal dendrites and the axon initial segment. 35,52,87,107 In neuronal networks of the hippocampus proper, fast-spiking PV þ interneurons form numerous GABAergic synaptic contacts to pyramidal cells in the perisomatic region 23,87 ( Figures 1C-E). As outlined above, these synapses are strongly and rhythmically activated during fast network oscillations, and multiple lines of evidence indicate that this phasic inhibition is a key factor in coordinating neuronal activity during network states such as gamma oscillations or sharp wave-ripple complexes.…”