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Background and Purpose: Select neuroactive steroids tune neural activity by modulating excitatory and inhibitory neurotransmission, including the endogenous cholesterol metabolite 24(S)‐hydroxycholesterol (24(S)‐HC), which is an N‐methyl‐d‐aspartate (NMDA) receptor positive allosteric modulator (PAM). NMDA receptor PAMs are potentially an effective pharmacotherapeutic strategy to treat conditions associated with NMDA receptor hypofunction. Experimental Approach: Using in vitro and in vivo electrophysiological recording experiments and behavioural approaches, we evaluated the effect of SAGE‐718, a novel neuroactive steroid NMDA receptor PAM currently in clinical development for the treatment of cognitive impairment, on NMDA receptor function and endpoints that are altered by NMDA receptor hypoactivity and assessed its safety profile. Key Results: SAGE‐718 potentiated GluN1/GluN2A‐D NMDA receptors with equipotency and increased NMDA receptor excitatory postsynaptic potential (EPSP) amplitude without affecting decay kinetics in striatal medium spiny neurons. SAGE‐718 increased the rate of unblock of the NMDA receptor open channel blocker ketamine on GluN1/GluN2A in vitro and accelerated the rate of return on the ketamine‐evoked increase in gamma frequency band power, as measured with electroencephalogram (EEG), suggesting that PAM activity is driven by increased channel open probability. SAGE‐718 ameliorated deficits due to NMDA receptor hypofunction, including social deficits induced by subchronic administration of phencyclidine, and behavioural and electrophysiological deficits from cholesterol and 24(S)‐HC depletion caused by 7‐dehydrocholesterol reductase inhibition. Finally, SAGE‐718 did not produce epileptiform activity in a seizure model or neurodegeneration following chronic dosing. Conclusions and Implications: These findings provide strong evidence that SAGE‐718 is a neuroactive steroid NMDA receptor PAM with a mechanism that is well suited as a treatment for conditions associated with NMDA receptor hypofunction. [ABSTRACT FROM AUTHOR]

Neuroactive steroids (NASs) have potent anxiolytic, anticonvulsant, sedative, and hypnotic actions, that reflect in part their efficacy as GABA A R positive allosteric modulators (PAM). In addition to this, NAS exert metabotropic effects on GABAergic inhibition via the activation of membrane progesterone receptors (mPRs), which are G-protein coupled receptors. mPR activation enhances the phosphorylation of residues serine 408 and 409 (S408/9) in the β3 subunit of GABA A Rs, increasing their accumulation in the plasma membrane leading to a sustained increase in tonic inhibition. To explore the significance of NAS-induced phosphorylation of GABA A Rs, we used mice in which S408/9 in the β3 subunit have been mutated to alanines, mutations that prevent the metabotropic actions of NASs on GABA A R function while preserving NAS allosteric potentiation of GABAergic current. While the sedative actions of NAS were comparable to WT, their anxiolytic actions were reduced in S408/9A mice. Although the induction of hypnosis by NAS were maintained in the mutant mice the duration of the loss of righting reflex was significantly shortened. Finally, ability of NAS to terminate diazepam pharmacoresistant seizures was abolished in S408/9A mice. In conclusion, our results suggest that S408/9 in the GABA A R β3 subunit contribute to the anxiolytic and anticonvulsant efficacy of NAS, in addition to their ability to regulate the loss of righting reflex. [ABSTRACT FROM AUTHOR]

Benzodiazepine drugs, through interaction with GABAAα1, GABAAα2,3, and GABAAα5 subunits, modulate cortical network oscillations, as reflected by a complex signature in the EEG power spectrum. Recent drug discovery efforts have developed GABAAα2,3-subunit-selective partial modulators in an effort to dissociate the side effect liabilities from the efficacy imparted by benzodiazepines. Here, we evaluated rat EEG and behavioral end points during dosing of nine chemically distinct compounds that we confirmed statistically to selectively to enhance GABAAα2,3-mediated vs. GABAAα1 or GABAAα5 currents in voltage clamped oocytes transfected with those GABAA subunits. These compounds were shown with in vivo receptor occupancy techniques to competitively displace [³H]flumazenil in multiple brain regions following peripheral administration at increasing doses. Over the same dose range, the compounds all produced dose-dependent EEG spectral power increases in the β- and and γ-bands. Finally, the dose range that increased γ-power coincided with that eliciting punished over unpunished responding in a behavioral conflict model of anxiety, indicative of anxiolysis without sedation. EEG y-band power increases showed a significant positive correlation to in vitro GABAAα2,3 modulatory intrinsic activity across the compound set, further supporting a hypothesis that this EEG signature was linked specifically to pharmacological modulation of GABAAα,3 signaling. These findings encourage further evaluation of this EEG signature as a noninvasive clinical translational biomarker that could ultimately facilitate development of GABAAα,3-subtype-selective drugs for anxiety and potentially other indications. [ABSTRACT FROM AUTHOR]

N-methyl-D-aspartate receptors (NMDARs) are glutamate-gated ion channels that are critical to the regulation of excitatory synaptic function in the CNS. NMDARs govern experience-dependent synaptic plasticity and have been implicated in the pathophysiology of various neuropsychiatric disorders including the cognitive deficits of schizophrenia and certain forms of autism. Certain neurosteroids modulateNMDARsexperimentally but their low potency, poor selectivity, and very low brain concentrations make them poor candidates as endogenous ligands or therapeutic agents. Hereweshow that the major brain-derived cholesterol metabolite 24(S)-hydroxycholesterol (24(S)-HC) is a very potent, direct, and selective positive allosteric modulator ofNMDARswith a mechanism that does not overlap that of other allosteric modulators. At submicromolar concentrations 24(S)-HC potentiates NMDAR-mediated EPSCs in rat hippocampal neurons but fails to affect AMPAR or GABAA receptors (GABAARs)-mediated responses. Cholesterol itself and other naturally occurring oxysterols present in brain do not modulateNMDARsat concentrations≤10μM. In hippocampal slices, 24(S)-HC enhances the ability of subthreshold stimuli to induce long-term potentiation (LTP). 24(S)-HC also reverses hippocampal LTP deficits induced by the NMDAR channel blocker ketamine. Finally, we show that synthetic drug-like derivatives of 24(S)-HC, which potently enhance NMDAR-mediated EPSCs and LTP, restore behavioral and cognitive deficits in rodents treated withNMDARchannel blockers. Thus, 24(S)-HC may function as an endogenous modulator of NMDARs acting at a novel oxysterol modulatory site that also represents a target for therapeutic drug development. [ABSTRACT FROM AUTHOR]

The significance of the mismatch negativity (MMN), an event-related potential measured in humans which indexes novelty in the auditory environment, has motivated a search for a cellular correlate of this process. A leading candidate is stimulus-specific adaptation (SSA) in auditory cortex units, which shares several characteristics with the MMN. Whether auditory cortex responses encode sensory novelty, a defining property of the MMN, however, has not been resolved. To evaluate this key issue, we used several variations of the auditory oddball paradigm from the human literature and examined psychophysical and pharmacological properties of multiunit activity in the auditory cortex of awake rodents. We found converging evidence dissociating SSA from sensory novelty and the MMN. First, during an oddball paradigm with frequency deviants, neuronal responses showed clear SSA but failed to encode novelty in a manner analogous to the human MMN. Second, oddball paradigms using intensity or duration deviants revealed a pattern of unit responses that showed sensory adaptation, but again without any measurable novelty correlates aligning to the human MMN. Finally NMDA antagonists, which are known to disrupt the MMN, suppressed the magnitude of multiunit responses in a nonspecific manner, leaving the process of SSA intact. Together, our results suggest that auditory novelty detection as indexed by the MMN is dissociable from SSA at the level of activity encoded by auditory cortex neurons. Further, the NMDA sensitivity reported for the MMN, which models the disruption of MMN observed in schizophrenia, may occur at a mechanistic locus outside of SSA. [ABSTRACT FROM AUTHOR]

The significance of the mismatch negativity (MMN), an event-related potential measured in humans which indexes novelty in the auditory environment, has motivated a search for a cellular correlate of this process. A leading candidate is stimulus-specific adaptation (SSA) in auditory cortex units, which shares several characteristics with the MMN. Whether auditory cortex responses encode sensory novelty, a defining property of the MMN, however, has not been resolved. To evaluate this key issue, we used several variations of the auditory oddball paradigm from the human literature and examined psychophysical and pharmacological properties of multiunit activity in the auditory cortex of awake rodents. We found converging evidence dissociating SSA from sensory novelty and the MMN. First, during an oddball paradigm with frequency deviants, neuronal responses showed clear SSA but failed to encode novelty in a manner analogous to the human MMN. Second, oddball paradigms using intensity or duration deviants revealed a pattern of unit responses that showed sensory adaptation, but again without any measurable novelty correlates aligning to the human MMN. Finally NMDA antagonists, which are known to disrupt the MMN, suppressed the magnitude of multiunit responses in a nonspecific manner, leaving the process of SSA intact. Together, our results suggest that auditory novelty detection as indexed by theMMNis dissociable from SSA at the level of activity encoded by auditory cortex neurons. Further, the NMDA sensitivity reported for the MMN, which models the disruption of MMN observed in schizophrenia, may occur at a mechanistic locus outside of SSA. [ABSTRACT FROM AUTHOR]

M1 muscarinic acetylcholine receptors (mAChRs) may represent a viable target for treatment of disorders involving impaired cognitive function. However, a major limitation to testing this hypothesis has been a lack of highly selective ligands for individual mAChR subtypes. We now report the rigorous molecular characterization of a novel compound, benzylquinolone carboxylic acid (BQCA), which acts as a potent, highly selective positive allosteric modulator (PAM) of the ratM1 receptor. This compound does not directly activate the receptor, but acts at an allosteric site to increase functional responses to orthosteric agonists. Radioligand binding studies revealed that BQCA increasesM1 receptor affinity for acetylcholine. We found that activation of the M1 receptor by BQC Ainduces a robust inward current and increases spontaneous EPSCs in medial prefrontal cortex (mPFC) pyramidal cells, effects which are absent in acute slices from M1 receptor knock-out mice. Furthermore, to determine the effect of BQCA on intact and functioning brain circuits, multiple single-unit recordings were obtained from the mPFC of rats that showed BQCA increases firing of mPFC pyramidal cells in vivo. BQCA also restored discrimination reversal learning in a transgenic mouse model of Alzheimer's disease and was found to regulate non-amyloidogenic APP processing in vitro, suggesting that M1 receptor PAMs have the potential to provide both symptomatic and disease modifying effects in Alzheimer's disease patients. Together, these studies provide compelling evidence that M1 receptor activation induces a dramatic excitation of PFC neurons and suggest that selectively activating the M1 mAChR subtype may ameliorate impairments in cognitive function. [ABSTRACT FROM AUTHOR]

Presents the highlights of the annual meeting of the American Epilepsy Society held in Philadelphia, Pennsylvania. Date of the event; Participant of the meeting; Program and activities of the congress; Theme of the convention.