D-serine reconstitutes synaptic and intrinsic inhibitory control of pyramidal neurons in a neurodevelopmental mouse model for schizophrenia.

The hypothesis of N-methyl-D-aspartate receptor (NMDAR) dysfunction for cognitive impairment in schizophrenia constitutes the theoretical basis for the translational application of NMDAR co-agonist D-serine or its analogs. However, the cellular mechanism underlying the therapeutic effect of D-serine remains unclear. In this study, we utilize a mouse neurodevelopmental model for schizophrenia that mimics prenatal pathogenesis and exhibits hypoexcitability of parvalbumin-positive (PV) neurons, as well as PV-preferential NMDAR dysfunction. We find that D-serine restores excitation/inhibition balance by reconstituting both synaptic and intrinsic inhibitory control of cingulate pyramidal neurons through facilitating PV excitability and activating small-conductance Ca2+-activated K+ (SK) channels in pyramidal neurons, respectively. Either amplifying inhibitory drive via directly strengthening PV neuron activity or inhibiting pyramidal excitability via activating SK channels is sufficient to improve cognitive function in this model. These findings unveil a dual mechanism for how D-serine improves cognitive function in this model.

The effects of serotonergic psychedelics in synaptic and intrinsic properties of neurons in layer II/III of the orbitofrontal cortex.

RATIONALE: Serotonergic psychedelics show promise in the treatment of psychiatric disorders, including obsessive-compulsive disorder. Dysfunction of the orbitofrontal cortex (OFc) has been implicated in the pathophysiology of compulsive behavior, which might be a key region for the efficacy of psychedelics. However, the effects of psychedelics on the neural activities and local excitation/inhibition (E/I) balance in the OFc are unclear. OBJECTIVES: This study aimed to investigate how 25C-NBOMe, a substituted phenethylamine psychedelic, regulated the synaptic and intrinsic properties of neurons in layer II/III of the OFc. METHODS: Acute brain slices containing the OFc of adult male Sprague Dawley rats were used for ex vivo whole-cell recording. The synaptic and intrinsic properties of neurons were monitored using voltage and current clamps, respectively. Electrically evoked action potential (eAP) was used to measure synaptic-driven pyramidal activity. RESULTS: 25C-NBOMe enhanced spontaneous neurotransmission at glutamatergic synapses but diminished that in GABAergic synapses through the 5-HT2A receptor. 25C-NBOMe also increased both evoked excitatory currents and evoked action potentials. Moreover, 25C-NBOMe promoted the excitability of pyramidal neurons but not fast-spiking neurons. Either inhibiting G protein-gated inwardly rectifying potassium channels or activating protein kinase C significantly obstructed the facilitative effect of 25C-NBOMe on the intrinsic excitability of pyramidal neurons. CONCLUSIONS: This work reveals the multiple roles of 25C-NBOMe in modulating synaptic and neuronal function in the OFc, which collectively promotes local E/I ratios.

The high frequency oscillation in orbitofrontal cortex is susceptible to phenethylamine psychedelic 25C-NBOMe in male rats.

Serotoninergic psychedelics induced extensive alterations in perception and cognition, which has been attributable to its disruptive effect on oscillatory rhythms of prefrontal cortex. However, there is a lack of information how serotoninergic psychedelics affect the intra-prefrontal network, which intrinsically interact to accomplish perceptual processing. Uncovering the altered neural network caused by psychedelics helps to understand the mechanisms of their psychoactive effects and contribute to develop biological markers of psychedelic effects. In present study, we investigated the effects of substituted phenethylamine psychedelic 25C-NBOMe on neural oscillations in the intra-prefrontal and hippocampal-prefrontal network. The effective dose of 25C-NBOMe (0.1 mg/kg) disrupting sensorimotor gating in male Sprague-Dawley rats was used to observe its effects on neural oscillations in the prelimbic cortex, anterior cingulate cortex, orbitofrontal cortex (OFC) and hippocampus CA1. The power of high frequency oscillation (HFO, 120-150 Hz) was potentiated by 25C-NBOMe selectively in the OFC, with peaking at 20-30 min after treatment. 25C-NBOMe strengthened HFO coherence within the intra-prefrontal, rather than hippocampal-prefrontal network. Potentiated HFO in the OFC had a strong positive correlation with the strengthened inter-prefrontal HFO coherence by 25C-NBOMe. The 25C-NBOMe-induced alterations of rhythmic patterns were prevented by pre-treatment with selective serotonin 2A receptor antagonist MDL100,907. These results demonstrate that OFC rhythmic activity in HFO is relatively susceptible to substituted phenethylamine and potentially drives drug-induced rhythmic coherence within intra-prefrontal regions. Our findings provide additional insight into the neuropathophysiology of the psychoactive effects of psychedelics and indicate that the altered HFO might be applied as a potential biological marker of psychedelic effect.

Enduring effects of juvenile social isolation on physiological properties of medium spiny neurons in nucleus accumbens.

RATIONALE: Juvenile social isolation (SI) and neglect is associated with a wide range of psychiatric disorders. While dysfunction of the corticolimbic pathway is considered to link various abnormal behaviors in SI models of schizophrenia, the enduring effects of early social deprivation on physiological properties of medium spiny neurons (MSNs) in nucleus accumbens (NAc) are not well understood. OBJECTIVES: This study investigated the impacts of juvenile SI on locomotor activity to methamphetamine (METH) and neurophysiological characteristics of MSNs in the core of NAc. METHODS: Socially isolated C57BL/6 mice experienced single housing for 4 weeks on postnatal day (PND) 21. The locomotor response to METH (1.0 mg/kg) was observed in both socially isolated and group-housed mice at PND 56. The effects of juvenile SI on the excitatory synaptic events in MSNs and the intrinsic excitability of MSNs in NAc core were investigated in other batches during PND 63-70. RESULTS: Socially isolated mice showed locomotor hypersensitivity to METH, although the expression of locomotor sensitization to METH in socially isolated mice was not different from group-housed mice. The recordings from MSNs of SI-reared mice exhibited higher frequency and smaller amplitude of miniature/spontaneous excitatory postsynaptic current than those from group-reared mice. Moreover, SI resulted in increased intrinsic excitability of MSNs in adult mice. CONCLUSIONS: These results demonstrate neuronal hyperactivity in the NAc of socially isolated mice, which could contribute to locomotor hypersensitivity to METH. Furthermore, the findings indicate a biological link between early negative life events and the vulnerability to psychostimulant-induced psychosis in adulthood.