Properties and dynamics of inhibitory synaptic communication within the CA3 microcircuits of pyramidal cells and interneurons expressing parvalbumin or cholecystokinin

Abstract

Key pointsr To understand how a network operates, its elements must be identified and characterized, and the interactions of the elements need to be studied in detail.r In the present study, we describe quantitatively the connectivity of two classes of inhibitory neurons in the hippocampal CA3 area (parvalbumin-positive and cholecystokinin-positive interneurons), a key region for the generation of behaviourally relevant synchronous activity patterns.r We describe how interactions among these inhibitory cells and their local excitatory target neurons evolve over the course of physiological and pathological activity patterns.r The results of the present study enable the construction of precise neuronal network models that may help us understand how network dynamics is generated and how it can underlie information processing and pathological conditions in the brain.r We show how inhibitory dynamics between parvalbumin-positive basket cells and pyramidal cells could contribute to sharp wave-ripple generation.Abstract Different hippocampal activity patterns are determined primarily by the interaction of excitatory cells and different types of interneurons. To understand the mechanisms underlying the generation of different network dynamics, the properties of synaptic transmission need to be uncovered. Perisomatic inhibition is critical for the generation of sharp wave-ripples, gamma oscillations and pathological epileptic activities. Therefore, we aimed to quantitatively and systematically characterize the temporal properties of the synaptic transmission between perisomatic inhibitory neurons and pyramidal cells in the CA3 area of mouse hippocampal slices, using action potential patterns recorded during physiological and pathological network states. Parvalbumin-positive (PV+) and cholecystokinin-positive (CCK+) interneurons showed distinct intrinsic physiological features. Interneurons of the same type formed reciprocally connected subnetworks, whereas the connectivity between interneuron classes was sparse. The characteristics of unitary interactions depended on the identity of both synaptic partners, whereas the short-term plasticity of synaptic transmission depended mainly on the presynaptic cell type. PV+ interneurons showed frequency-dependent depression, whereas more complex dynamics characterized the output of CCK+ interneurons. We quantitatively captured the dynamics of transmission at these different types of connection with simple mathematical models, and describe in detail the response to physiological and pathological discharge patterns. Our data suggest that the temporal propeties of PV+ interneuron transmission may contribute to sharp wave-ripple generation.

Synapsin II Regulation of GABAergic Synaptic Transmission Is Dependent on Interneuron Subtype

“…However, there is strong evidence that an excitation/inhibition imbalance in presymptomatic animals contributes to the initial epilepsy predisposition (Boido et al, 2010;Fassio et al, 2011;Farisello et al, 2013;Feliciano et al, 2013). In the present study, we demonstrated that SynII deletion reduced IPSC amplitudes and prolonged the release kinetics in PV interneurons, which have a key role in the regulation of seizure propagation (Krook-Magnuson et al, 2013;Sessolo et al, 2015). Furthermore, extensive evidence links epilepsy with asynchronous activity of GABAergic synapses through tonic inhibition (Jiang et al, 2012;Pandit et al, 2013;Medrihan et al, 2015).…”

“…The other parameters include the CA, the coefficient of variation (CV) of synaptic currents, the paired pulse ratio (PPR), and the failure rate (FR) of synaptic transmission (Neu et al, 2007;Daw et al, 2009;Bartos and Elgueta, 2012;Hu et al, 2014). A recent study demonstrated that cluster analysis can be used to classify these interneuron subtypes according to their intrinsic synaptic and spiking properties (Kohus et al, 2016). We conducted cluster analysis based upon five variables, including spiking (SF and CA) and synaptic (CV, FR, and PPR) parameters ( Fig.…”

“…Synapsins I and II (SynI and SynII) are neuronal phosphoproteins that reversibly associate with synaptic vesicles and tether them to the cytomatrix to maintain a reserve pool of vesicles (Greengard et al, 1993;Shupliakov et al, 2011). Converging basic and clinical work has convincingly implicated the synapsins in the pathophysiology of epilepsy.…”

“…At the clinical level, genetic epidemiology studies have identified a human nonsense mutation in the SynI gene associated with syndromic epilepsy (Garcia et al, 2004;Giannandrea et al, 2013) and also a contribution of SynII to a sporadic epilepsy predisposition (Cavalleri et al, 2007;Lakhan et al, 2010;Prasad et al, 2014). At the basic science level, experiments in genetically modified animals have shown that deletion of either the SynI or SynII genes results in a strong epileptic phenotype (Li et al, 1995;Rosahl et al, 1995;Etholm and Heggelund, 2009). Thus, understanding how deletion of the synapsins affects neuronal networks in the brain has a potential to illuminate key aspects of the pathophysiology of some forms of epilepsy.…”

Synaptic Reorganization of the Perisomatic Inhibitory Network in Hippocampi of Temporal Lobe Epileptic Patients

“…In contrast, CB1-positive basket cells receive large amount of subcortical inputs carrying information about the “inner world” of the brain [7] and modulate synchronous ensemble activity accordingly. Therefore, PV-positive basket cells are thought to function as “clockworks” for cortical network oscillations, whereas CB1-expressing interneurons operate as a “plastic fine-tuning device.” Perisomatic inhibition has an important role in the generation and regulation of sharp wave-ripples [8], gamma oscillations [9], and seizure-like activities [10] in rodent hippocampal slice preparations. The first attempts have been made to achieve seizure-control via manipulation of perisomatic inhibition in animal models, by selectively stimulate PV-positive neurons and by transplanting interneuron precursors [11–13].…”