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

Cell type-specific separation of subicular principal neurons during network activities.

The hippocampal output structure, the subiculum, expresses two major memory relevant network rhythms, sharp wave ripple and gamma frequency oscillations. To this date, it remains unclear how the two distinct types of subicular principal cells, intrinsically bursting and regular spiking neurons, participate in these two network rhythms. Using concomitant local field potential and intracellular recordings in an in vitro mouse model that allows the investigation of both network rhythms, we found a cell type-specific segregation of principal neurons into participating intrinsically bursting and non-participating regular spiking cells. However, if regular spiking cells were kept at a more depolarized level, they did participate in a specific manner, suggesting a potential bimodal working model dependent on the level of excitation. Furthermore, intrinsically bursting and regular spiking cells exhibited divergent intrinsic membrane and synaptic properties in the active network. Thus, our results suggest a cell-type-specific segregation of principal cells into two separate groups during network activities, supporting the idea of two parallel streams of information processing within the subiculum

Gamma frequency network oscillations within the subiculum.

<p>(A) Gamma frequency oscillations were found in all of the examined subicular regions (middle, ventral, and dorsal). Sketches illustrate horizontal (middle, ventral and dorsal) slice preparation. The position of the scissors indicate the cuts made around the perimeters of the subicular region with the resulting subicular minislices marked by an asterisk. (A, right next to the sketch) Two example LFP recordings obtained from intact (grey, I, top trace) and isolated (black, II, bottom trace) middle (top), ventral (middle) and dorsal (bottom) slices are displayed together with the corresponding power spectra (A, middle column, color code according to the example traces). (A, right) The population data of the oscillatory frequency (top histogram) and spectral power (bottom histogram) exhibits no significant difference of the intact compared to the isolated subicular slices in network oscillatory gamma frequency as well as in spectral power (values and numbers in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123636#pone.0123636.t001" target="_blank">Table 1</a>) except for the ventral subicular slices (<i>p</i> = 0.034, significance level indicated by asterisk). (B) Gamma frequency oscillations recorded from the medial (grey, I) and lateral (black, II) subiculum within the sagittal slice preparations. Same type of illustration as in (<i>A</i>), the subicular region is marked by an asterisk. The population histogram for frequency and power (values and numbers in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123636#pone.0123636.t002" target="_blank">Table 2</a>) did not reveal a significant difference.</p

Electrophysiological properties of subicular PCs.

<p>Electrophysiological properties of subicular PCs.</p

Behavior of subicular RS cells during spontaneous subicular SPW activity.

<p>(A) Neuronal discharge pattern and microphotograph of an RS cell. RS cells do not fire bursts and show little or no sag potential. They respond to a depolarizing current injection with a train of single APs. RS cells show a typical pyramidal cell morphology. (A, right) The accommodation behavior (n = 19 IB cells; n = 16 RS cells) reveals a significant difference between subicular IB and RS cells (level of significance indicated by the asterisks, <i>p</i> < 0.0001). (B) Example of a RS cell at RMP (top left) and under the condition of depolarizing current injection (bottom left) during spontaneous SPW is given with the same type of illustration as in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0123636#pone.0123636.g003" target="_blank">Fig 3</a>. Intracellular example recording of a silent RS cell at RMP (top left) depicting a SPW associated postsynaptic depolarization without AP generation. The population data (n = 7, right next) do not contain any APs, but aggregate a phase-locked mixed postsynaptic current (PSP) instead. When depolarized by current injection previously silent RS cells display a tonic AP firing mode (bottom left). In stark contrast to the IB cells, data of spontaneous active and depolarized RS cells reveal a prominent SPW peak correlated pause of AP generation (n = 11, bottom, middle left). EPSPs and IPSPs examples are displayed in correlation to the LFP (middle right). The EPSPs and IPSPs were recorded at −80 mV and at 0 mV, respectively. (right) Accumulated mean EPSP/IPSP with respect to the maximum SPW peak deflection. (C) EPSP (left) and IPSP (right) amplitudes for both cell classes. IB cells receive significantly higher synaptic excitation than RS neurons (indicated by the asterisk, <i>p</i> = 0.033; IB: n = 12; RS: n = 13), while there was no significant difference in IPSP (<i>p</i> = 0.52; IB: n = 3; RS: n = 4).</p

Electrophysiological properties of subicular PCs during gamma frequency oscillations.

<p>Electrophysiological properties of subicular PCs during gamma frequency oscillations.</p

Sharp wave and gamma network oscillations within the subiculum.

<p>(A) Spectrogram (top) with color-coded power spectral density (PSD) exemplifies the transition from spontaneously occurring sharp wave-ripples (SWR) to gamma frequency oscillations within the subiculum. The corresponding LFP recordings are displayed below. The application of kainic acid (KA, onset is marked by black line) abolishes the SWR rhythm and induces, after a brief transitory state, a stable oscillatory gamma rhythm. The recording interruptions of the top spectrograms and the underlying LFP traces are 12 s (middle) and 25 min (right). Red lines mark three examples that are illustrated below with higher temporal resolution (SWR, transition, gamma). (A, bottom, left) The SWR (filtered 2–300 Hz), the corresponding SPW (2–50 Hz) and the ripple components (100–300 Hz) supplemented by the color-coded power spectral density wavelet transform. (A, bottom, right) The boxplot depicts the distribution of the wavelet peak power spectral frequencies of 100 analyzed consecutive ripple events of the upper example trace. (B) Sharp waves of both polarities are exemplified on the left with each SWR trace (2–300 Hz, top), the ripple trace (100–300 Hz, middle) and the corresponding wavelet transform as color-coded power spectral density plot (bottom). The boxplot (right) illustrates the distribution of the mean SWP rates of all slices investigated (n = 42).</p

Temporal correlation of subicular RS cell activity to gamma frequency network oscillations.

<p>(A) Examples of simultaneous LFP (top) and intracellular (bottom) recordings during gamma frequency oscillations. In stark contrast to IB neurons, without current injection RS cells usually do not generate APs during gamma frequency oscillations and the data (n = 7) solely reveals a phase-locked mixed postsynaptic current (PSP, middle left). A depolarizing current injection initiates AP generation (middle right). Depolarized and spontaneous active RS cells (n = 9) show a distribution of AP generation (right) similar to the one observed in IB cells. (B) Example traces of synaptic potentials on the left. EPSP and IPSP were recorded at −80 mV and 0 mV respectively. Maximal cumulative postsynaptic potential peak deflections occur before the maximum of LFP gamma cycle. (C) There was no significant difference between the two classes of subicular PCs concerning the EPSP (IB: n = 8, RS: n = 11; <i>p</i> = 0.86) and IPSP amplitude (IB: n = 5, RS: n = 5; <i>p</i> = 0.56).</p