The translationally relevant mouse model of the 15q13.3 microdeletion syndrome reveals deficits in neuronal spike firing matching clinical neurophysiological biomarkers seen in schizophrenia

Abstract

AimTo date, the understanding and development of novel treatments for mental illness is hampered by inadequate animal models. For instance, it is unclear to what extent commonly used behavioural tests in animals can inform us on the mental and affective aspects of schizophrenia.MethodsTo link pathophysiological processes in an animal model to clinical findings, we have here utilized the recently developed Df(h15q13)/+ mouse model for detailed investigations of cortical neuronal engagement during pre‐attentive processing of auditory information from two back‐translational auditory paradigms. We also investigate if compromised putative fast‐spiking interneurone (FSI) function can be restored through pharmacological intervention using the Kv3.1 channel opener RE1. Chronic multi‐array electrodes in primary auditory cortex were used to record single cell firing from putative pyramidal and FSI in awake animals during processing of auditory sensory information.ResultsWe find a decreased amplitude in the response to auditory stimuli and reduced recruitment of neurones to fast steady‐state gamma oscillatory activity. These results resemble encephalography recordings in patients with schizophrenia. Furthermore, the probability of interneurones to fire with low interspike intervals during 80 Hz auditory stimulation was reduced in Df(h15q13)/+ mice, an effect that was partially reversed by the Kv3.1 channel modulator, RE1.ConclusionThis study offers insight into the consequences on a neuronal level of carrying the 15q13.3 microdeletion. Furthermore, it points to deficient functioning of interneurones as a potential pathophysiological mechanism in schizophrenia and suggests a therapeutic potential of Kv3.1 channel openers.

Electrophysiological evidence for defective fast‐spiking GABAergic neurones in a schizophrenia model

“…The finding by Thelin et al . (), which reveals a defective high‐frequency repetitive firing of fast‐spiking neurones in a mouse model of the 15q13.3 microdeletion syndrome, is consistent with the finding of reduced K v 3.1 mRNA levels in schizophrenia, and highlights the importance of fast‐spiking neurone dysfunction in schizophrenia.…”

“…A clear reduction in mean firing rate of pyramidal neurones during the 80‐Hz ASSR stimuli appeared in the Df(h15q13)/+ mice in Thelin et al . (), which may mimic the evoked ASSR deficit in patients with schizophrenia. On the other hand, there is an increase in spontaneous or resting‐state power of gamma band oscillations, which has also been consistently reported in schizophrenia.…”

“…Thelin et al . () recorded in vivo task‐related spike firings of individual neurones in the primary auditory cortex in a mouse model of the 15q13.3 microdeletion syndrome, which is associated with an approx. 10‐fold increased risk for developing schizophrenia.…”

Light and darkness in circadian rhythms

“…For high-quality studies on both experimental animals and human subjects, authors are already considering (and later discussing) circadian and rhythmic influences on the design and outcome of their studies in, for example cardiovascular 13 and neurophysiology. 14 The same is true for pharmacological interventions, 15 which often, on the one hand, influence biological rhythms, while their biological effects and pharmacokinetics may, in turn, be modulated by biorhythms. 16 In mammalian metabolism, circadian rhythms assume a role that is indisputably unique.…”

Models

“…Diabetic animal and cell models as well as models of the metabolic syndrome serve for studying various aspects of this group of diseases . Moreover, models have been created for neurologic and even psychiatric diseases . Human disease models include not only models of different genesis (genetic, operative and feeding) but also of different complexity including cell, organ and whole animal models.…”