Increasing the Excitatory Drive Rescues Excitatory/Inhibitory Imbalance and Mismatch Negativity Deficit Caused by Parvalbumin Specific GluA1 Deletion.

Disturbance in synaptic excitatory and inhibitory (E/I) transmission in the prefrontal cortex is considered a critical factor for cognitive dysfunction, a core symptom in schizophrenia. However, the cortical network pathophysiology induced by E/I imbalance is not well characterized, and an effective therapeutic strategy is lacking. In this study, we simulated imbalanced cortical network by using mice with parvalbumin neuron (PV) specific knockout of GluA1 (AMPA receptor subunit 1) (Gria1-PV KO) as an experimental model. Applying high-content confocal imaging and electrophysiological recordings in the medial prefrontal cortex (mPFC), we found structural and functional alterations in the local network of Gria1-PV KO mice. Additionally, we applied electroencephalography (EEG) to assess potential deficits in mismatch negativity (MMN), the standard readout in the clinic for measuring deviance detection and sensory information processing. Gria1-PV KO animals exhibited abnormal theta oscillation and MMN, which is consistent with clinical findings in cognitively impaired patients. Remarkably, we demonstrated that the glycine transporter 1 (GlyT1) inhibitor, Bitopertin, ameliorates E/I imbalance, hyperexcitability, and sensory processing malfunction in Gria1-PV KO mice. Our results suggest that PV-specific deletion of GluA1 might be an experimental approach for back translating the E/I imbalance observed in schizophrenic patients. Our work offers a systematic workflow to understand the effect of GlyT1 inhibition in restoring cortical network activity from single cells to local brain circuitry. This study highlights that selectively boosting NMDA receptor-mediated excitatory drive to enhance the network inhibitory transmission from interneurons to pyramidal neurons (PYs) is a potential therapeutic strategy for restoring E/I imbalance-associated cognitive-related abnormality.

Where have all the Orais gone? Commentary on "Orai1 channels are essential for amplification of glutamate-evoked Ca2+ signals in dendritic spines to regulate working and associative memory".

Orai1 channels were reported as critical contributors to the Ca2+ signal in hippocampal neurons underlying synaptic plasticity associated with learning and memory. We discuss the results in view of conflicting other reports that stressed the roles of Orai2 channels but failed to detect functions of Orai1 channels in these neurons.

Two types of functionally distinct Ca2+ stores in hippocampal neurons.

It is widely assumed that inositol trisphosphate (IP3) and ryanodine (Ry) receptors share the same Ca2+ pool in central mammalian neurons. We now demonstrate that in hippocampal CA1 pyramidal neurons IP3- and Ry-receptors are associated with two functionally distinct intracellular Ca2+ stores, respectively. While the IP3-sensitive Ca2+ store refilling requires Orai2 channels, Ry-sensitive Ca2+ store refilling involves voltage-gated Ca2+ channels (VGCCs). Our findings have direct implications for the understanding of function and plasticity in these central mammalian neurons.

A vicious cycle of ß amyloid-dependent neuronal hyperactivation.

ß-amyloid (Aß)-dependent neuronal hyperactivity is believed to contribute to the circuit dysfunction that characterizes the early stages of Alzheimer's disease (AD). Although experimental evidence in support of this hypothesis continues to accrue, the underlying pathological mechanisms are not well understood. In this experiment, we used mouse models of Aß-amyloidosis to show that hyperactivation is initiated by the suppression of glutamate reuptake. Hyperactivity occurred in neurons with preexisting baseline activity, whereas inactive neurons were generally resistant to Aß-mediated hyperactivation. Aß-containing AD brain extracts and purified Aß dimers were able to sustain this vicious cycle. Our findings suggest a cellular mechanism of Aß-dependent neuronal dysfunction that can be active before plaque formation.