Disparate insults relevant to schizophrenia converge on impaired spike synchrony and weaker synaptic interactions in prefrontal local circuits

A prefrontal network model operating near steady and oscillatory states links spike desynchronization and synaptic deficits in schizophrenia

“…To investigate how loss of NMDAR synaptic function may distort the physiological dynamics of prefrontal circuits causing those circuits to fail in schizophrenia, and to provide an explanation for biological phenomena we recently observed in monkey prefrontal cortex (Kummerfeld et al, 2020;Zick et al, 2021Zick et al, , 2018, we developed a theoretical framework employing a sparsely connected recurrent network model accounting for AMPAR, NMDAR, and GABAR mediated synaptic currents. We used this platform to investigate how spike timing dynamics in the network depended on the interplay between synaptic conductances, and more specifically, how spike timing was distorted by the loss of NMDAR synaptic function.…”

“…Given that in our neural recording data spiking synchrony peaks around the time of the motor response and the following reward (Zick et al, 2018), and that it is likely to gate synaptic plasticity through Hebbian (Dan and Poo, 2004) and dopamine-dependent (He et al, 2015;Kasai et al, 2021;Yagishita et al, 2014) mechanisms, behavior-timed modulations of circuit dynamics likely play a critical role in structuring synaptic connectivity in prefrontal networks and, therefore, in learning and cognitive function. Correspondingly, given that NMDAR blockage results in the reduction of spiking synchrony on the millisecond time scale (Zick et al, 2018), NMDAR synaptic deficits in schizophrenia would be expected to disconnect prefrontal cortical networks via an activity-dependent process in schizophrenia (Dan and Poo, 2004;Kummerfeld et al, 2020;Uhlhaas and Singer, 2015;Zick et al, 2021Zick et al, , 2018 leading to cognitive impairment. This is a novel pathogenic mechanism with significant implications both for what drives disease and what might slow or reverse it, even after chronic illness.…”

“…We do not yet have a clear understanding of how or why this occurs, particularly at the cellular and synaptic level, where critical changes in cell and synaptic function lead to wide-scale failure of networks. To help fill this gap in knowledge, we have developed parallel nonhuman primate (Kummerfeld et al, 2020;Zick et al, 2018) and mouse genetic models (Zick et al, 2021) of prefrontal network failure in schizophrenia and used extracellular neural recording in these models to describe how insults associated with schizophrenia impact neural dynamics in prefrontal local circuits. We found that diverse insults operating through different molecular mechanisms (blocking NMDAR in primates or deleting a schizophrenia risk gene in mice related to miRNA processing) led to the same endpoint in prefrontal cortex: both perturbations reduced 0-lag synchronous spiking between prefrontal neurons along with a reduction in the amount of information transmitted by synaptic interactions between the neurons (Kummerfeld et al, 2020;Zick et al, 2021Zick et al, , 2018.…”

“…To help fill this gap in knowledge, we have developed parallel nonhuman primate (Kummerfeld et al, 2020;Zick et al, 2018) and mouse genetic models (Zick et al, 2021) of prefrontal network failure in schizophrenia and used extracellular neural recording in these models to describe how insults associated with schizophrenia impact neural dynamics in prefrontal local circuits. We found that diverse insults operating through different molecular mechanisms (blocking NMDAR in primates or deleting a schizophrenia risk gene in mice related to miRNA processing) led to the same endpoint in prefrontal cortex: both perturbations reduced 0-lag synchronous spiking between prefrontal neurons along with a reduction in the amount of information transmitted by synaptic interactions between the neurons (Kummerfeld et al, 2020;Zick et al, 2021Zick et al, , 2018. This work suggests that multiple risk factors produce convergent effects on prefrontal networks during schizophrenia pathogenesis, but they do not address how or why molecular disruptions of cell function lead to the distortions of network dynamics that we have observed in monkey prefrontal cortex, and that in humans are likely responsible for the failure of prefrontal circuits and ultimately the cognitive deficits in the disease (Jauhar et al, 2022).…”

“…Synchronous, or near synchronous spiking in pre-and postsynaptic neurons governs spike timing dependent synaptic plasticity (Dan and Poo, 2004). Thus, any insult or perturbation (either of genetic, developmental, or environmental origin) that disrupts the balance between NMDAR synaptic inputs, oscillatory activity and spike timing in prefrontal local circuits could ultimately cause these circuits to actively disconnect via spike-timing dependent synaptic plasticity, contributing to disease progression (Zick et al, 2021(Zick et al, , 2018. Additionally, recent evidence suggests that synchronous pre-and postsynaptic spiking establishes an eligibility trace at specific dendritic spines rendering them susceptible to potentiation by subsequent dopamine (He et al, 2015;Kasai et al, 2021;Yagishita et al, 2014).…”