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Inhibitory control is essential for the regulation of neuronal network activity, where excitatory and inhibitory synapses can act synergistically, reciprocally, and antagonistically. Sustained excitation-inhibition (E-I) balance, therefore, relies on the orchestrated adjustment of excitatory and inhibitory synaptic strength. While growing evidence indicates that the brain's extracellular matrix (ECM) is a crucial regulator of excitatory synapse plasticity, it remains unclear whether and how the ECM contributes to inhibitory control in neuronal networks. Here we studied the simultaneous changes in excitatory and inhibitory connectivity after ECM depletion. We demonstrate that the ECM supports the maintenance of E-I balance by retaining inhibitory connectivity. Quantification of synapses and super-resolution microscopy showed that depletion of the ECM in mature neuronal networks preferentially decreases the density of inhibitory synapses and the size of individual inhibitory postsynaptic scaffolds. The reduction of inhibitory synapse density is partially compensated by the homeostatically increasing synaptic strength via the reduction of presynaptic GABA B receptors, as indicated by patch-clamp measurements and GABA B receptor expression quantifications. However, both spiking and bursting activity in neuronal networks is increased after ECM depletion, as indicated by multi-electrode recordings. With computational modelling, we determined that ECM depletion reduces the inhibitory connectivity to an extent that the inhibitory synapse scaling does not fully compensate for the reduced inhibitory synapse density. Our results indicate that the brain's ECM preserves the balanced state of neuronal networks by supporting inhibitory control via inhibitory synapse stabilization, which expands the current understanding of brain activity regulation.

Hippocampal ripple oscillations likely support reactivation of memory traces that manifest themselves as temporally organized spiking of sparse neuronal ensembles. However, the network mechanisms concurring to achieve this function are largely unknown. We designed a multi-compartmental model of the CA3-CA1 subfields to generate biophysically realistic ripple dynamics from the cellular level to local field potentials. Simulations broadly parallel in vivo observations and support that ripples emerge from CA1 pyramidal spiking paced by recurrent inhibition. In addition to ripple oscillations, key coordination mechanisms involve concomitant aspects of network activity. Recurrent synaptic interactions in CA1 exhibit slow-gamma band coherence with CA3 input, thus offering a way to coordinate CA1 activities with CA3 inducers. Moreover, CA1 feedback inhibition controls the content of spontaneous replay during CA1 ripples, forming new mnemonic representations through plasticity. These insights are consistent with slow-gamma interactions and interneuronal circuit plasticity observed in vivo, suggesting a multifaceted ripple-related replay phenomenon., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Sharp wave‐ripples (140–220 Hz) are patterns of brain activity observed in the local field potential of the hippocampus which are present during memory consolidation. As rodents switch from memory consolidation to memory encoding behaviors, cholinergic inputs to the hippocampus from neurons in the medial septum‐diagonal band of Broca cause a marked reduction in ripple incidence. The mechanism for this disruption in ripple power is not fully understood. In isolated neurons, the major effect of cholinergic input on hippocampal neurons is depolarization of the membrane potential, which affects both hippocampal pyramidal neurons and inhibitory interneurons. Using an existing model of ripple‐frequency oscillations that includes both pyramidal neurons and interneurons, we investigated the mechanism whereby depolarizing inputs to these neurons can affect ripple power and frequency. We observed that ripple power and frequency are maintained, as long as inputs to pyramidal neurons and interneurons are balanced. Preferential drive to pyramidal neurons or interneurons, however, affects ripple power and can disrupt ripple oscillations by pushing ripple frequency higher or lower. Thus, an imbalance in drive to pyramidal neurons and interneurons provides a means whereby cholinergic input can suppress hippocampal ripples. [ABSTRACT FROM AUTHOR]

An increasing number of epilepsy patients are afflicted with drug-resistant temporal lobe epilepsy (TLE) and require alternative therapeutic approaches. High-affinity glycine receptors (haGlyRs) are functionally adapted to tonic inhibition due to their response to hippocampal ambient glycine, and their synthesis is activity-dependent. Therefore, in our study, we scanned TLE hippocampectomies for expression of haGlyRs and characterized the effects mediated by these receptors using primary hippocampal neurons. Increased haGlyR expression occurred in TLE hippocampi obtained from patients with a severe course of disease. Furthermore, in TLE patients, haGlyR and potassium chloride cotransporter 2 (KCC2) expressions were inversely regulated. To examine this potential causal relationship with respect to TLE histopathology, we established a hippocampal cell culture system utilising tonic inhibition mediated by haGlyRs in response to hippocampal ambient glycine and in the context of a high Cl- equilibrium potential, as is the case in TLE hippocampal neurons. We showed that hypoactive neurons increase their ratio between glutamatergic and GABAergic synapses, reduce their dendrite length and finally undergo excitotoxicity. Pharmacological dissection of the underlying processes revealed ionotropic glutamate and TrkB receptors as critical mediators between neuronal hypoactivity and the emergence of these TLE-characteristic histopathological signs. Moreover, our results indicate a beneficial role for KCC2, because decreasing the Cl- equilibrium potential by KCC2 expression also rescued hypoactive hippocampal neurons. Thus, our data support a causal relationship between increased haGlyR expression and the emergence of histopathological TLE-characteristic signs, and they establish a pathophysiological role for neuronal hypoactivity in the context of a high Cl- equilibrium potential. [ABSTRACT FROM AUTHOR]