Keith G. Phillips

Decoupling of sleep-dependent cortical and hippocampal interactions in a neurodevelopmental model of schizophrenia.

Summary Rhythmic neural network activity patterns are defining features of sleep, but interdependencies between limbic and cortical oscillations at different frequencies and their functional roles have not been fully resolved. This is particularly important given evidence linking abnormal sleep architecture and memory consolidation in psychiatric diseases. Using EEG, local field potential (LFP), and unit recordings in rats, we show that anteroposterior propagation of neocortical slow-waves coordinates timing of hippocampal ripples and prefrontal cortical spindles during NREM sleep. This coordination is selectively disrupted in a rat neurodevelopmental model of schizophrenia: fragmented NREM sleep and impaired slow-wave propagation in the model culminate in deficient ripple-spindle coordination and disrupted spike timing, potentially as a consequence of interneuronal abnormalities reflected by reduced parvalbumin expression. These data further define the interrelationships among slow-wave, spindle, and ripple events, indicating that sleep disturbances may be associated with state-dependent decoupling of hippocampal and cortical circuits in psychiatric diseases.

Differential effects of NMDA antagonists on high frequency and gamma EEG oscillations in a neurodevelopmental model of schizophrenia

Neuroanatomical, electrophysiological and behavioural abnormalities following timed prenatal methylazoxymethanol acetate (MAM) treatment in rats model changes observed in schizophrenia. In particular, MAM treatment on gestational day 17 (E17) preferentially disrupts limbic-cortical circuits, and is a promising animal model of schizophrenia. The hypersensitivity of this model to the NMDA receptor antagonist-induced hyperactivity has been proposed to mimic the increase in sensitivity observed in schizophrenia patients following PCP and Ketamine administration. However, how this increase in sensitivity in both patients and animals translates to differences in EEG oscillatory activity is unknown. In this study we have shown that MAM-E17 treated animals have an increased response to the hyperlocomotor and wake promoting effects of Ketamine, PCP, and MK801 but not to the competitive antagonist SDZ 220,581. These behavioural changes were accompanied by altered EEG responses to the NMDAR antagonists, most evident in the gamma and high frequency (HFO) ranges; altered sensitivity of these neuronal network oscillations in MAM-exposed rats is regionally selective, and reflects altered interneuronal function in this neurodevelopmental model.

GABAB receptor modulators potentiate baclofen‐induced depression of dopamine neuron activity in the rat ventral tegmental area

1 2,6‐Di‐tert‐butyl‐4‐(3‐hydroxy‐2,2‐dimethyl‐propyl)‐phenol (CGP7930) is a recently reported positive allosteric modulator of γ‐aminobutyric acid (GABA)B receptors. In this study, we assessed the ability of CGP7930 to modulate the baclofen‐induced depression of dopamine (DA) neuron activity via the activation of GABAB receptors in the ventral tegmental area in rat midbrain slices. 2 The selective GABAB receptor agonist, baclofen, depressed the spontaneous firing rate of DA neurons in a concentration‐dependent manner (EC50=0.27 μM, n=11). CGP7930 (30 μM) significantly (P<0.05) shifted the baclofen concentration–response curve to the left (EC50=0.15 μM, n=5). The effects of baclofen alone or baclofen coapplied with CGP7930 were fully blocked by 1 μM (2S)‐3‐[[(1S)‐1‐(3,4‐dichloropheny)ethyl]amino‐2‐hydroxypropyl] (phenylmethyl) phosphinic acid (CGP55845), a potent and selective GABAB receptor antagonist. 3 In similar experiments, N‐[3,3‐diphenylpropyl]‐α‐methylbenzylamine (fendiline) (30 or 50 μM), a compound shown to potentiate GABAB receptor‐mediated cortical hyperpolarisation, also significantly enhanced the inhibitory effect of baclofen. 4 It is therefore concluded that the recently reported GABAB receptor modulators, CGP7930 and fendiline, can enhance GABAB receptor‐mediated depression of DA neuronal activity. This finding suggests a therapeutic potential for GABAB potentiators for the treatment of diseases associated with a hyperfunctional mesocorticolimbic system.

The nicotinic α4β2 receptor selective agonist, TC-2559, increases dopamine neuronal activity in the ventral tegmental area of rat midbrain slices

Abstract The ability of α4β2 nicotinic acetylcholine receptors to modulate dopaminergic (DA) cell activity in the ventral tegmental area (VTA) in rat midbrain slices was assessed using a selective α4β2 receptor agonist, TC-2559 ((E)-N-methyl-4-[3-(5-ethoxypyridin)y1]-3-buten-1-amine). The selectivity of TC-2559 was characterized across 6 recombinant human nicotinic receptors (α4β2, α2β4, α4β4, α3β4, α3β2 and α7) stably expressed in mammalian cell lines. Using a fluorescent imaging plate reader and fluo-3 to monitor changes in intracellular calcium, TC-2559 was found to be at least 69 fold more potent on α4β2 than on other heteromeric subtypes, with an efficacy of 33%. No activity on the homomeric α7 subtype was detected. TC-2559 also showed selectivity for α4β2 over the α4β4 and α7 subtypes expressed in Xenopus oocytes. When bath applied to VTA slices, TC-2559 increased the firing of DA cells in a dose-dependent manner, in the same concentration range that activates α4β2 receptors in recombinant cell lines or oocytes. The effect of TC-2559 was blocked by 2 μM dihydro-β-erythroidine (an α4β2-preferring antagonist), but not by 10 nM methyllycaconitine (an α7 antagonist). Glutamate receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione and D(−)-2-amino-5-phosphonopentanoic acid) did not reduce TC-2559-induced responses, suggesting that the increase in DA cell firing induced by TC-2559 is caused by direct postsynaptic depolarisation via the activation of α4β2 receptors and not by enhancement of glutamate release.

Phenotypic characterization of nonsocial behavioral impairment in neurexin 1α knockout rats.

Neurexins are neuronal presynaptic proteins that play a key role in mediation of synapse formation. Heterozygous partial deletions in the neurexin-1 gene (NRXN1, 2p16.3) have been observed in autism spectrum disorder (ASD) patients. NRXN1-α knockout (KO) mice present behavioral impairments that resemble some of the core ASD symptoms of social impairment and inflexibility/stereotypy. At present, a thorough assessment of cognitive function has yet to be completed. Rats, containing a biallelic deletion of the NRNX1-α gene on a Sprague Dawley background were compared to littermate wild types across a range of tasks designed to test functional domains disrupted in ASD and other neurodevelopmental disorders, including sensory perception (prepulse inhibition), attention (latent inhibition), associative learning (instrumental and Pavlovian conditioning), and memory (rewarded alternation T maze and spatial discrimination). NRXN1α KO rats were found to present with large and persistent nonsocial deficits, including hyperactivity, deficits in simple instrumental learning, latent inhibition, and spatial-dependent learning. No deficit in sensorimotor gating was observed, despite the presence of an exaggerated startle response. Although KO animals were also able to learn a simple Pavlovian conditioning discrimination, they did display impaired latent inhibition. The presence of pronounced impairments in several domains in NRXN1α KO rats clearly suggests that nonsocial cognitive deficits can also be measured in an animal model of ASD. Further exploration of those deficits, both clinically and preclinically, as planned in the Innovative Medicines Initiatives European Autism Interventions: A Multicenter Study for Developing New Medications program, may help to better understand the brain circuitry involved in ASD and therefore open new avenues to advance novel therapies.

Neural oscillations as a translational tool in schizophrenia research: Rationale, paradigms and challenges

Neural oscillations have received recently a great deal of interest in schizophrenia research because of the possibility to integrate findings from non-invasive electro/magnetoencephalographical recordings with pre-clinical research, which could potentially lead to the identification of pathophysiological mechanisms and novel treatment targets. In the current paper, we review the potential as well as the challenges of this approach by summarizing findings on alterations in rhythmic activity from both animal models and human data which have implicated dysfunctional neural oscillations in the explanation of cognitive deficits and certain clinical symptoms of schizophrenia. Specifically, we will focus on findings that have examined neural oscillations during 1) perceptual processing, 2) working memory and executive processes and 3) spontaneous activity. The importance of the development of paradigms suitable for human and animal models is discussed as well as the search for mechanistic explanation for oscillatory dysfunctions.

Coordinated acetylcholine release in prefrontal cortex and hippocampus is associated with arousal and reward on distinct timescales

Summary Cholinergic neurotransmission throughout the neocortex and hippocampus regulates arousal, learning, and attention. However, owing to the poorly characterized timing and location of acetylcholine release, its detailed behavioral functions remain unclear. Using electrochemical biosensors chronically implanted in mice, we made continuous measurements of the spatiotemporal dynamics of acetylcholine release across multiple behavioral states. We found that tonic levels of acetylcholine release were coordinated between the prefrontal cortex and hippocampus and maximal during training on a rewarded working memory task. Tonic release also increased during REM sleep but was contingent on subsequent wakefulness. In contrast, coordinated phasic acetylcholine release occurred only during the memory task and was strongly localized to reward delivery areas without being contingent on trial outcome. These results show that coordinated acetylcholine release between the prefrontal cortex and hippocampus is associated with reward and arousal on distinct timescales, providing dual mechanisms to support learned behavior acquisition during cognitive task performance.

Electrical and network neuronal properties are preferentially disrupted in dorsal, but not ventral, medial entorhinal cortex in a mouse model of Tauopathy

The entorhinal cortex (EC) is one of the first areas to be disrupted in neurodegenerative diseases such as Alzheimers disease and frontotemporal dementia. The responsiveness of individual neurons to electrical and environmental stimuli varies along the dorsal–ventral axis of the medial EC (mEC) in a manner that suggests this topographical organization plays a key role in neural encoding of geometric space. We examined the cellular properties of layer II mEC stellate neurons (mEC-SCs) in rTg4510 mice, a rodent model of neurodegeneration. Dorsoventral gradients in certain intrinsic membrane properties, such as membrane capacitance and afterhyperpolarizations, were flattened in rTg4510 mEC-SCs, while other cellular gradients [e.g., input resistance (Ri), action potential properties] remained intact. Specifically, the intrinsic properties of rTg4510 mEC-SCs in dorsal aspects of the mEC were preferentially affected, such that action potential firing patterns in dorsal mEC-SCs were altered, while those in ventral mEC-SCs were unaffected. We also found that neuronal oscillations in the gamma frequency band (30–80 Hz) were preferentially disrupted in the dorsal mEC of rTg4510 slices, while those in ventral regions were comparatively preserved. These alterations corresponded to a flattened dorsoventral gradient in theta-gamma cross-frequency coupling of local field potentials recorded from the mEC of freely moving rTg4510 mice. These differences were not paralleled by changes to the dorsoventral gradient in parvalbumin staining or neurodegeneration. We propose that the selective disruption to dorsal mECs, and the resultant flattening of certain dorsoventral gradients, may contribute to disturbances in spatial information processing observed in this model of dementia. SIGNIFICANCE STATEMENT The medial entorhinal cortex (mEC) plays a key role in spatial memory and is one of the first areas to express the pathological features of dementia. Neurons of the mEC are anatomically arranged to express functional dorsoventral gradients in a variety of neuronal properties, including grid cell firing field spacing, which is thought to encode geometric scale. We have investigated the effects of tau pathology on functional dorsoventral gradients in the mEC. Using electrophysiological approaches, we have shown that, in a transgenic mouse model of dementia, the functional properties of the dorsal mEC are preferentially disrupted, resulting in a flattening of some dorsoventral gradients. Our data suggest that neural signals arising in the mEC will have a reduced spatial content in dementia.

The subtype-selective nicotinic acetylcholine receptor positive allosteric potentiator 2087101 differentially facilitates neurotransmission in the brain

Positive allosteric modulators of centrally expressed nicotinic acetylcholine receptors have therapeutic potentials in areas of cognition, motor function and reward. Several chemical classes of allosteric modulators that are selective for alpha7 nicotinic receptors have been characterised, but potentiators for the most widely expressed alpha4beta2 nicotinic receptor subtype are few and less defined, owing probably to the difficulty to achieve selectivity over other heteromeric receptor subtypes. 2087101 (2-amino-5-keto)thiazole) is a potent potentiator of both alpha7 and alpha4beta2 receptors and it has selectivity against the alpha3beta4 subtype, which may be responsible for the undesirable peripheral side effects. To further characterise its ability to differentiate between native nicotinic receptors, we examined the effects of 2087101 on alpha7, alpha4beta2* and alpha3beta4* receptor-mediated responses in the rat brain in electrophysiological and neurochemical experiments. 2087101 significantly potentiated agonist-induced, alpha7 and non-alpha7 receptor-mediated, GABAergic postsynaptic currents in cultured hippocampal neurones, but not the nicotine-stimulated [(3)H]noradrenaline release from hippocampal slices, which was primarily mediated by alpha3beta4* receptors, confirming its selectivity for alpha7 and alpha4beta2* receptors in native systems. 2087101 also significantly enhanced nicotine-stimulated firing increase in dopamine neurones of the ventral tegmental area, an effect that was dihydro-beta-erythroidine-sensitive and thereby mediated by alpha4beta2* nicotinic receptors. 2087101 can therefore enhance native nicotinic activities mediated by alpha7 and alpha4beta2*, but not alpha3beta4* receptors, showing its unique ability to discriminate between native heteromeric nicotinic receptor subtypes and its therapeutic potential for treating brain disorders by concurrent modulation of both alpha7 and alpha4beta2* nicotinic receptors.

Partial agonists for α4β2 nicotinic receptors stimulate dopaminergic neuron firing with relatively enhanced maximal effects

BACKGROUND AND PURPOSE Partial agonists selective for α4β2 nicotinic ACh receptors have been developed for smoking cessation as they induce weak activation of native α4β2* receptors and inhibit effect of nicotine. However, it is unclear whether at brain functions there is an existence of receptor reserve that allows weak receptor activation to induce maximum physiological effects. We assessed the extent of α4β2 partial agonist‐induced increase of firing rate in dopaminergic neurons and evaluated the influence of receptor reserve.