Ben Grayson

Background: Voltage-gated Kv3.1 and KV3.2 potassium channels are mainly located on parvalbumin (PV) containing interneurons, where they play a key role in synchronising the coordinated firing of pyramidal neurons and regulating cognitive function. Aims: We aim to explore the efficacy of acute treatment with AUT00206 (5,5-dimethyl-3-[2-(7-methylspiro[2H-benzofuran-3,1'-me]-4-yl)oxypyrimidin-5-yl]imidazolidine-2,4-dione), a novel and selective positive modulator of Kv3.1/3.2 channels, to improve cognitive and social behaviour deficits in our validated animal model relevant to schizophrenia. Methods: Female Lister Hooded rats were treated with phencyclidine for 7 days, followed by a 7-day washout (scPCP). The efficacy of AUT00206 was tested in the novel object recognition (NOR), reversal learning (RL) and social interaction (SI) paradigms. Results: The cognitive and social behaviour deficits induced by scPCP were significantly attenuated by AUT00206 (10 and 30 mg/kg) in the three behavioural tasks. These data demonstrate, for the first time, the efficacy of a novel Kv3.1/3.2 channel modulator, AUT00206, in two cognitive domains (short-term recognition memory and an aspect of cognitive flexibility) and an aspect of negative symptoms in a validated animal model of schizophrenia symptomatology. Conclusions: Modulation of Kv3.1/3.2 channels on PV interneurons could be an important novel approach for the treatment of schizophrenia.

Background: Schizophrenia is a serious psychiatric disorder that affects over 24 million people worldwide. Current therapies treat positive symptoms but show little efficacy for negative and cognitive symptoms, which can impact quality of life. Development of effective medication for this unmet medical need is imperative. Phytocannabinoids, such as cannabidivarin (CBDV), show promising results for the treatment of neurological disorders and have demonstrated efficacy in preclinical models, including seizure, autism, Rett, and Fragile X syndromes. Aim: To determine the effect of CBDV on cognitive and social deficits in a sub-chronic phencyclidine (scPCP) rat model of relevance to schizophrenia. Methods: Female Lister Hooded rats received scPCP (2 mg/kg, intraperitoneally (i.p.)) or saline for 7 days, followed by a minimum 7-day drug-free washout. Rats were then treated with saline, CBDV (2, 10, and 20 mg/kg, i.p.), or risperidone (0.1 mg/kg, i.p.) 60 minutes before novel object recognition (NOR), social interaction (SI), and reversal learning (RL) testing. Results: scPCP significantly impaired performance in all three behavioural tests. Deficits in the NOR and SI tests were significantly improved by CBDV (10 and 20 mg/kg), while 20 mg/kg was effective at reversing the deficits in RL. Risperidone also significantly reversed the scPCP-induced deficit in the NOR, RL, and SI paradigms. Conclusion: Here, we are the first to demonstrate the ability of CBDV to ameliorate cognitive and social deficits in the scPCP rat model of relevance for schizophrenia, suggesting further research is justified into the potential therapeutic benefits of CBDV in patients.

The cognitive deficits of schizophrenia are linked to imbalanced excitatory and inhibitory signalling in the prefrontal cortex (PFC), disrupting gamma oscillations. We previously demonstrated that two mGlu5 receptor-positive allosteric modulators (PAMs), VU0409551 and VU0360172, restore cognitive deficits in the sub-chronic PCP (scPCP) rodent model for schizophrenia via distinct changes in PFC intracellular signalling molecules. Here, we have assessed ex vivo gamma oscillatory activity in PFC slices from scPCP rats and investigated the effects of VU0409551 and VU0360172 upon oscillatory power. mGlu5 receptor, protein kinase C (PKC), and phospholipase C (PLC) inhibition were also used to examine ‘modulation bias’ in PAM activity. The amplitude and area power of gamma oscillations were significantly diminished in the scPCP model. Slice incubation with either VU0409551 or VU0360172 rescued scPCP-induced oscillatory deficits in a concentration-dependent manner. MTEP blocked the PAM-induced restoration of oscillatory power, confirming the requirement of mGlu5 receptor modulation. Whilst PLC inhibition prevented the power increase mediated by both PAMs, PKC inhibition diminished the effects of VU0360172 but not VU0409551. This aligns with previous reports that VU0409551 exhibits preferential activation of the phosphatidylinositol-3-kinase (PI3K) signalling pathway over the PKC cascade. Restoration of the excitatory/inhibitory signalling balance and gamma oscillations may therefore underlie the mGluR5 PAM-mediated correction of scPCP-induced cognitive deficits.

Treatments for schizophrenia are not effective in ameliorating cognitive deficits. Therefore, novel therapies are needed to treat cognitive impairments associated with schizophrenia (CIAS), which are modelled in rats through administration of sub-chronic phencyclidine (scPCP). We have previously shown that enrichment via voluntary exercise prevents and reverses impairments in novel object recognition (NOR) in this model.The present study aimed to investigate if handling could prevent delay-induced NOR deficits and prevent and reverse scPCP-induced NOR deficits.Two cohorts of adult female Lister Hooded rats were used throughout. In experiment one, handling (five minutes/day, five days/week for two weeks), took place before scPCP administration (2mg/kg, i.p. twice daily for seven days). NOR tests were conducted at two, four, and seven weeks post-handling with a one-minute inter-trial interval (ITI) and at five weeks post-dosing with a six-hour ITI. In experiment two, animals were handled after scPCP administration and were tested immediately in the one-minute ITI NOR task and again at two weeks post-handling.In both handling regimens, the PCP-Control groups failed to discriminate novelty, conversely the PCP-Handled groups significantly discriminated in this task. In the 6h ITI test, Vehicle and PCP-Controls failed to discriminate novelty; however, the Vehicle and PCP-Handled groups did significantly discriminate.Handling rats prevented the delay induced NOR deficits and prevented and reversed scPCP-induced deficits in NOR. These findings add to evidence that environmental enrichment is a viable treatment for cognitive deficits in animal tests and models of relevance to schizophrenia, with potential to translate into effective treatments for CIAS.

Schizophrenia is a complex psychopathology whose treatment is still challenging. Given the limitations of existing antipsychotics, there is urgent need for novel drugs with fewer side effects. SEP-363856 (SEP-856) is a novel psychotropic agent currently under phase III clinical investigation for schizophrenia treatment. In this study, we investigated the ability of an acute oral SEP-856 administration to modulate the functional activity of specific brain regions at basal levels and under glutamatergic or dopaminergic-perturbed conditions in adult rats. We found that immediate-early genes (IEGs) expression was strongly upregulated in the prefrontal cortex and, to a less extent, in the ventral hippocampus, suggesting an activation of these regions. Furthermore, SEP-856 was effective in preventing the hyperactivity induced by an acute injection of phencyclidine (PCP), but not of d-amphetamine (AMPH). The compound effectively normalized the PCP-induced increase in IEGs expression in the PFC at all doses tested, whereas only the highest dose determined the major modulations on AMPH-induced changes. Lastly, SEP-856 acute administration corrected the cognitive deficits produced by subchronic PCP administration. Taken together, our data provide further insights on SEP-856, suggesting that modulation of the PFC may represent an important mechanism for the functional and behavioural activity of this novel compound.

Cognitive dysfunction and negative symptoms of schizophrenia remain an unmet clinical need. Therefore, it is essential that new treatments and approaches are developed to recover the cognitive and social impairments that are seen in patients with schizophrenia. These may only be discovered through the use of carefully validated, aetiologically relevant and translational animal models. With recent renewed interest in the neurodevelopmental hypothesis of schizophrenia, postnatal administration of N-methyl-D-aspartate receptor (NMDAR) antagonists such as phencyclidine (PCP) has been proposed as a model that can mimic aspects of schizophrenia pathophysiology. The purpose of the current review is to examine the validity of this model and compare it with the adult subchronic PCP model. We review the ability of postnatal PCP administration to produce behaviours (specifically cognitive deficits) and neuropathology of relevance to schizophrenia and their subsequent reversal by pharmacological treatments. We review studies investigating effects of postnatal PCP on cognitive domains in schizophrenia in rats. Morris water maze and delayed spontaneous alternation tasks have been used for working memory, attentional set-shifting for executive function, social novelty discrimination for selective attention and prepulse inhibition of acoustic startle for sensorimotor gating. In addition, we review studies on locomotor activity and neuropathology. We also include two studies using dual hit models incorporating postnatal PCP and two studies on social behaviour deficits following postnatal PCP. Overall, the evidence we provide supports the use of postnatal PCP to model cognitive and neuropathological disturbances of relevance to schizophrenia. To date, there is a lack of evidence to support a significant advantage of postnatal PCP over the adult subchronic PCP model and full advantage has not been taken of its neurodevelopmental component. When thoroughly characterised, it is likely that it will provide a useful neurodevelopmental model to complement other models such as maternal immune activation, particularly when combined with other manipulations to produce dual or triple hit models. However, the developmental trajectory of behavioural and neuropathological changes induced by postnatal PCP and their relevance to schizophrenia must be carefully mapped out. Overall, we support further development of dual (or triple) hit models incorporating genetic, neurodevelopmental and appropriate environmental elements in the search for more aetiologically valid animal models of schizophrenia and neurodevelopmental disorders (NDDs).