In our model, reduced parvalbumin in synapses of fast-spiking interneurons affected network oscillations, and asynchronous release of GABA correlated with reduction of oscillatory power. One possibility is that the alteration in oscillatory activity occurred through increased asynchronous release of GABA (Manseau et al., 2010
). However, a direct causal link between asynchronous release and impaired gamma activity remains to be established. Asynchronous release of GABA increased the probability of synaptic release for hundreds of milliseconds following synaptic stimulation; thus, the inhibition was effectively extended in time. Börgers et al. (2005)
previously used computational models to show that temporally distributed inhibition (resulting from temporally asynchronous activity of interneurons) reduced the amplitude of the background gamma activity, impaired the response of the network to stimuli, and increased the distractability of the response, consistent with our observations of a reduced response to stimuli in networks with reduced PV in the interneurons. This mechanism does not necessarily require the activity of interneurons to be asynchronous, but rather depends on asynchronous synaptic transmission. Asynchronous spiking of interneurons may indeed act in concert with the synaptic mechanism studied here. The relative role of interneuron synchronization and asynchronous release of GABA in setting the network rhythm remains to be investigated.
The asynchronous release of neurotransmitter is present even at glutamatergic central synapses, which could also affect the dynamics of the network (Lau and Bi, 2005
; Jones et al., 2007
; Chang and Mennerick, 2010
; Manseau et al., 2010
). The propensity of a synapse to exhibit asynchronous release likely depends on spatial organization of the active zone and on the presence of calcium buffers with different kinetics/mobility (Nadkarni et al., 2010
). In the present study, we used a phenomenological approach to model the relation between synaptic calcium and asynchronous neurotransmitter release. Effects of active zone geometry, calcium diffusion, and buffer mobility were neglected. We anticipate that including these detailed features in the model (which comes at the expense of dramatically increased computational complexity) will not qualitatively change conclusions regarding the role of asynchronous release in mediating the effects of parvalbumin deficit on gamma range activity. How the complexity of synaptic microphysiology might affect the collective activity remains to be tested with more detailed models.
The spectral properties of collective oscillations in our model were strongly dependent on the strength and dynamics of the interactions between PY and IN subpopulations. More importantly, these results predict that the availability and release of synaptic GABA directly affect collective oscillations. In particular, the lack of PV at synaptic terminals of fast-spiking interneurons decreased gamma-band synchronization by increased asynchronous release of GABA.
Several studies have reported that stimulus-evoked collective oscillatory activity (assessed in a time window up to ~300 ms after stimulus presentation) was altered in schizophrenia patients (Ferrarelli et al., 2008
; Hirano et al., 2008
; Roach and Mathalon, 2008
; Spencer et al., 2008
; Uhlhaas and Singer, 2010
). Some studies showed that early evoked gamma-band response (50–150 ms after stimulus cessation) was reduced in schizophrenia (Hirano et al., 2008
; Roach and Mathalon, 2008
; Spencer et al., 2008
). In another study, gamma power was reduced only in a window 220–350 ms after a stimulus (Gallinat et al., 2004
). These differences could be explained in our model by the differing ability of the stimuli used in these studies to “switch on” asynchronous GABA release. In another study, the spectral power of evoked gamma-band oscillations was reduced in EEG recordings from frontal cortices of human schizophrenia patients (Ferrarelli et al., 2008
). Furthermore, a recent study found that PV expression correlates with reduction of evoked gamma oscillations in an animal model of the disease (Phillips et al., 2011
). These results, together with our modeling studies suggest that a deficit in parvalbumin expression in PV interneurons may partly explain the pathophysiology of schizophrenia.
Reduced inhibitory drive in schizophrenia has been attributed to reduced expression of GAD67, the enzyme responsible for most of the GABA synthesis in the brain (Akbarian and Huang, 2006
). A decreased inhibitory drive would intuitively lead to increased firing rates of both pyramidal neurons and interneurons. In our model, a reduction in the strength of the GABA “signal” to pyramidal neurons (implemented either as a reduction in peak synaptic conductance or as a more prolonged recovery from synaptic depression) () decreased the peak spectral power and shifted it toward higher frequencies. This network disinhibition was not dependent on PV concentration (). However, lowering the PV concentration decreased neuronal firing rates (). Thus, PV reduction may be a mechanism used by interneurons to maintain network homeostasis and to compensate for the increased firing rate incurred by a compromised GAD67 functionality. Interestingly, data from cultured neurons show that reduction in GAD67 is followed by the reduction in the PV content (Kinney et al., 2006
). Preliminary results of our model incorporating the dynamic homeostatic-like changes in both GABA conductance and PV concentration at synaptic terminals of PV+ interneurons support this possibility (data not shown).
Acute disinhibition of pyramidal neurons had been previously suggested as the underlying mechanism of the propsychotic effects of NMDAR antagonists such as phencyclidine and ketamine (Olney et al., 1999
; Homayoun and Moghaddam, 2007
). These antagonists induce psychotic symptoms in humans and trigger an outbreak in schizophrenia patients (Javitt and Zukin, 1991
; Krystal et al., 1994
). The heightened sensitivity of PV+ interneurons to NMDA antagonists (Homayoun and Moghaddam, 2007
) may be attributed to differences in NMDA receptor kinetics and expression in PY versus PV+ neurons (Wang and Gao, 2010
), and some modeling studies (Spencer, 2009
) support this. Our simulations further support disinhibition of the network following decreased GABA conductances.
It is important to note, however, that these acute effects of NMDAR antagonists do not produce the long-term alterations in parvalbumin and GAD67 expression modeled in our study (Behrens et al., 2007
). Nonetheless, the reduction in GAD67 and PV immunoreactivity in PV+ interneurons observed following prolonged application of NMDA antagonists suggests a critical role for NMDA transmission in the maintenance of proper GABAergic synaptic transmission (Kinney et al., 2006
; Behrens et al., 2007
; Zhang et al., 2008
). Indeed, several studies performed in mice with postnatal downregulation of NMDARs in PV interneurons have shown an increased sensitivity of the cortical network to the acute effects of NMDAR antagonist exposures (Belforte et al., 2010
; Carlen et al., 2011
). Furthermore, acute pharmacological blockade of NMDARs with several NMDAR antagonists in a neurodevelopmental animal model produced deficits in PV interneurons and decreased the evoked gamma power (Phillips et al., 2011
). These results strongly suggest that NMDA hypofunction and GABA dysfunction are part of the pathophysiological chain of events leading to the onset of schizophrenia.
Genetic disruption of NMDAR function in PV interneurons in the NMDAR ablation model produced an increased excitability of pyramidal neurons with increased spontaneous activity in the 30–80 Hz range (Belforte et al., 2010
; Korotkova et al., 2010
; Carlen et al., 2011
). Pilot studies performed with our model show that the relative spectral power of spontaneous activity in high beta and lower gamma range was increased when the NMDA conductance was set to zero on interneurons (the “spontaneous state” was achieved by reducing the external stimulation to both PY and IN neurons to produce firing rates of ~1–3 Hz in these neurons). The model further suggested that the NMDAR blockade-induced increase in the relative spectral power was weaker for a network with deficit in PV concentration, consistent with the recent experimental findings suggesting the same trend in animal models (Phillips et al., 2011
). More detailed modeling studies, incorporating small differences in NMDA subunit composition between PY and PV+ neurons, will further delineate the interaction of NMDA hypofunction and dysfunctional GABA transmission in schizophrenia.
Although PV reduction can account for some of the changes reported in schizophrenia and related neuropsychiatric disorders, several other alterations in neural circuitry are well documented in schizophrenia. As discussed above, the changes in GAD67 expression, as well as the reduced excitatory drive supporting the hypothesis of NMDA hypofunction should be incorporated in the model to obtain a full picture of the alterations observed in schizophrenia. Nonetheless, a deficit in PV may be an important step leading to other pathological dynamics associated with schizophrenia. How these different processes interact to reproduce the full etiology and pathology of schizophrenia remains to be investigated in joint experimental and modeling studies.