Altered Excitatory-Inhibitory Balance in the NMDA-Hypofunction Model of Schizophrenia

Schizophrenia is a common psychiatric disorder of high incidence, affecting approximately 1% of the world population. The essential neurotransmitter pathology of schizophrenia remains poorly defined, despite huge advances over the past half-century in identifying neurochemical and pathological abnormalities in the disease. The dopamine/serotonin hypothesis has originally provided much of the momentum for neurochemical research in schizophrenia. In recent years, the attention has, however, shifted to the glutamate system, the major excitatory neurotransmitter in the CNS and towards a concept of functional imbalance between excitatory and inhibitory transmission at the network level in various brain regions in schizophrenia. The evidence indicating a central role for the NMDA-receptor subtype in the aetiology of schizophrenia has led to the NMDA-hypofunction model of this disease and the use of phencyclidines as a means to induce the NMDA-hypofunction state in animal models. The purpose of this review is to discuss recent findings highlighting the importance of the NMDA-hypofunction model of schizophrenia, both from a clinical perspective, as well as in opening a line of research, which enables electrophysiological studies at the cellular and network level in vitro. In particular, changes in excitation–inhibition (E/I) balance in the NMDA-hypofunction model of the disease and the resulting changes in network behaviours, particularly in gamma frequency oscillatory activity, will be discussed

Cell-specific synaptic plasticity induced by network oscillations

Gamma rhythms are known to contribute to the process of memory encoding. However, little is known about the underlying mechanisms at the molecular, cellular and network levels. Using local field potential recording in awake behaving mice and concomitant field potential and whole-cell recordings in slice preparations we found that gamma rhythms lead to activity-dependent modification of hippocampal networks, including alterations in sharp wave- ripple complexes. Network plasticity, expressed as long-lasting increases in sharp wave-associated synaptic currents, exhibits enhanced excitatory synaptic strength in pyramidal cells that is induced postsynaptically and depends on metabotropic glutamate receptor-5 activation. In sharp contrast, alteration of inhibitory synaptic strength is independent of postsynaptic activation and less pronounced. Further, we found a cell type-specific, directionally biased synaptic plasticity of two major types of GABAergic cells, parvalbumin- and cholecystokinin-expressing interneurons. Thus, we propose that gamma frequency oscillations represent a network state that introduces long-lasting synaptic plasticity in a cell-specific manner

GABA-enhanced collective behavior in neuronal axons underlies persistent gamma-frequency oscillations

Gamma (30–80 Hz) oscillations occur in mammalian electroencephalogram in a manner that indicates cognitive relevance. In vitro models of gamma oscillations demonstrate two forms of oscillation: one occurring transiently and driven by discrete afferent input and the second occurring persistently in response to activation of excitatory metabotropic receptors. The mechanism underlying persistent gamma oscillations has been suggested to involve gap-junctional communication between axons of principal neurons, but the precise relationship between this neuronal activity and the gamma oscillation has remained elusive. Here we demonstrate that gamma oscillations coexist with high-frequency oscillations (>90 Hz). High-frequency oscillations can be generated in the axonal plexus even when it is physically isolated from pyramidal cell bodies. They were enhanced in networks by nonsomatic -aminobutyric acid type A (GABAA) receptor activation, were modulated by perisomatic GABAA receptor-mediated synaptic input to principal cells, and provided the phasic input to interneurons required to generate persistent gamma-frequency oscillations. The data suggest that high-frequency oscillations occurred as a consequence of random activity within the axonal plexus. Interneurons provide a mechanism by which this random activity is both amplified and organized into a coherent network rhythm

Cell-type-specific modulation of feedback inhibition by serotonin in the hippocampus

Midbrain raphe nuclei provide strong serotonergic projections to the hippocampus, in which serotonin (5-HT) exerts differential effects mediated by multiple 5-HT receptor subtypes. The functional relevance of this diversity of information processing is poorly understood. Here we show that serotonin via 5-HT(1B) heteroreceptors substantially reduces synaptic excitation of cholecystokinin-expressing interneurons in area CA1 of the rat hippocampus, in contrast to parvalbumin-expressing basket cells. The reduction is input specific, affecting only glutamatergic synaptic transmission originating from CA1 pyramidal cells. As a result, serotonin selectively decreases feedback inhibition via 5-HT(1B) receptor activation and subsequently increases the integration time window for spike generation in CA1 pyramidal cells. Our data imply an important role for serotonergic modulation of GABAergic action in subcortical control of hippocampal output

Cell-type specific inhibition controls the high-frequency oscillations in the medial entorhinal cortex

The medial entorhinal cortex (mEC) plays a critical role for spatial navigation and memory. While many studies have investigated the principal neurons within the entorhinal cortex, much less is known about the inhibitory circuitries within this structure. Here, we describe for the first time in the mEC a subset of parvalbumin-positive (PV+) interneurons (INs)-stuttering cells (STUT)-with morphological, intrinsic electrophysiological, and synaptic properties distinct from fast-spiking PV+ INs. In contrast to the fast-spiking PV+ INs, the axon of the STUT INs also terminated in layer 3 and showed subthreshold membrane oscillations at gamma frequencies. Whereas the synaptic output of the STUT INs was only weakly reduced by a μ-opioid agonist, their inhibitory inputs were strongly suppressed. Given these properties, STUT are ideally suited to entrain gamma activity in the pyramidal cell population of the mEC. We propose that activation of the μ-opioid receptors decreases the GABA release from the PV+ INs onto the STUT, resulting in disinhibition of the STUT cell population and the consequent increase in network gamma power. We therefore suggest that the opioid system plays a critical role, mediated by STUT INs, in the neural signaling and oscillatory network activity within the mEC

Maintaining network activity in submerged hippocampal slices: importance of oxygen supply

Studies in brain slices have provided a wealth of data on the basic features of neurons and synapses. In the intact brain, these properties may be strongly influenced by ongoing network activity. Although physiologically realistic patterns of network activity have been successfully induced in brain slices maintained in interface-type recording chambers, they have been harder to obtain in submerged-type chambers, which offer significant experimental advantages, including fast exchange of pharmacological agents, visually guided patch-clamp recordings, and imaging techniques. Here, we investigated conditions for the emergence of network oscillations in submerged slices prepared from the hippocampus of rats and mice. We found that the local oxygen level is critical for generation and propagation of both spontaneously occurring sharp wave–ripple oscillations and cholinergically induced fast oscillations. We suggest three ways to improve the oxygen supply to slices under submerged conditions: (i) optimizing chamber design for laminar flow of superfusion fluid; (ii) increasing the flow rate of superfusion fluid; and (iii) superfusing both surfaces of the slice. These improvements to the recording conditions enable detailed studies of neurons under more realistic conditions of network activity, which are essential for a better understanding of neuronal network operation

Play and tickling responses map to the lateral columns of the rat periaqueductal gray

The persistence of play after decortication points to a subcortical mechanism of play control. We found that global blockade of the rat periaqueductal gray with either muscimol or lidocaine interfered with ticklishness and play. We recorded vocalizations and neural activity from the periaqueductal gray of young, playful rats during interspecific touch, play, and tickling. Rats vocalized weakly to touch and more strongly to play and tickling. Periaqueductal gray units showed diverse but strong modulation to tickling and play. Hierarchical clustering based on neuronal responses to play and tickling revealed functional clusters mapping to different periaqueductal gray columns. Specifically, we observed play-neutral/tickling-inhibited and tickling/play-neutral units in dorsolateral and dorsomedial periaqueductal gray columns. In contrast, strongly play/tickling-excited units mapped to the lateral columns and were suppressed by anxiogenic conditions. Optogenetic inactivation of lateral periaqueductal columns disrupted ticklishness and play. We conclude that the lateral periaqueductal gray columns are decisive for play and laughter

Coexpression of vesicular glutamate transporters 1 and 2, glutamic acid decarboxylase and calretinin in rat entorhinal cortex

We studied the distribution and coexpression of vesicular glutamate transporters (VGluT1, VGluT2), glutamic acid decarboxylase (GAD) and calretinin (CR, calcium-binding protein) in rat entorhinal cortex, using immunofluorescence staining and multichannel confocal laser scanning microscopy. Images were computer processed and subjected to automated 3D object recognition, colocalization analysis and 3D reconstruction. Since the VGluTs (in contrast to CR and GAD) occurred in fibers and axon terminals only, we focused our attention on these neuronal processes. An intense, punctate VGluT1-staining occurred everywhere in the entorhinal cortex. Our computer program resolved these punctae as small 3D objects. Also VGluT2 showed a punctate immunostaining pattern, yet with half the number of 3D objects per tissue volume compared with VGluT1, and with statistically significantly larger 3D objects. Both VGluTs were distributed homogeneously across cortical layers, with in MEA VGluT1 slightly more densely distributed than in LEA. The distribution pattern and the size distribution of GAD 3D objects resembled that of VGluT2. CR-immunopositive fibers were abundant in all cortical layers. In double-stained sections we noted ample colocalization of CR and VGluT2, whereas coexpression of CR and VGluT1 was nearly absent. Also in triple-staining experiments (VGluT2, GAD and CR combined) we noted coexpression of VGluT2 and CR and, in addition, frequent coexpression of GAD and CR. Modest colocalization occurred of VGluT2 and GAD, and incidental colocalization of all three markers. We conclude that the CR-containing axon terminals in the entorhinal cortex belong to at least two subpopulations of CR-neurons: a glutamatergic excitatory and a GABAergic inhibitory

Depression of glutamate and GABA release by presynaptic GABAB receptors in the entorhinal cortex in normal and chronically epileptic rats

Presynaptic GABAB receptors (GABABR) control glutamate and GABA release at many synapses in the nervous system. In the present study we used whole-cell patch-clamp recordings of spontaneous excitatory and inhibitory synaptic currents in the presence of TTX to monitor glutamate and GABA release from synapses in layer II and V of the rat entorhinal cortex (EC)in vitro. In both layers the release of both transmitters was reduced by application of GABABR agonists. Quantitatively, the depression of GABA release in layer II and layer V, and of glutamate release in layer V was similar, but glutamate release in layer II was depressed to a greater extent. The data suggest that the same GABABR may be present on both GABA and glutamate terminals in the EC, but that the heteroreceptor may show a greater level of expression in layer II. Studies with GABABR antagonists suggested that neither the auto- nor the heteroreceptor was consistently tonically activated by ambient GABA in the presence of TTX. Studies in EC slices from rats made chronically epileptic using a pilocarpine model of temporal lobe epilepsy revealed a reduced effectiveness of both auto- and heteroreceptor function in both layers. This could suggest that enhanced glutamate and GABA release in the EC may be associated with the development of the epileptic condition. Copyright © 2006 S. Karger AG