PT  - JOURNAL ARTICLE
AU  - Marzieh Funk
AU  - Niklas Schuelert
AU  - Stefan Jaeger
AU  - Cornelia Dorner-Ciossek
AU  - Holger Rosenbrock
AU  - Volker Mack
TI  - Activation of group II metabotropic receptors attenuates cortical E-I imbalance in a 15q13.3 microdeletion mouse model
AID  - 10.1101/2020.09.17.301259
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.09.17.301259
4099  - http://biorxiv.org/content/early/2020/09/17/2020.09.17.301259.short
4100  - http://biorxiv.org/content/early/2020/09/17/2020.09.17.301259.full
AB  - Animal models reflecting human risk for schizophrenia are essential research tools for gaining further insight into the convergence of CNS pathology and clinical biomarkers. Amongst the variety of animal models that display schizophrenia-related neuronal network deficits, transgenic mice for rare and highly penetrant copy number variants (CNVs) provide a unique opportunity to study pathological correlates in models with strong construct validity. The Df(h15q13)/+ mouse model of the human 15q13.3 microdeletion CNV has been shown to mimic deficits in parvalbumin positive (PV+) interneuron and cortical network function. However, the corresponding changes in synapse density and activity within the medial prefrontal cortex (mPFC) have not been described. Using high-content immunofluorescence imaging, we have shown a reduced density of PV+ neurons and inhibitory synapses in the mPFC of Df(h15q13)/+ mice. We found that the reduced detection of PV+ synapses were accompanied by changes in spontaneous inhibitory and excitatory synaptic activity onto layer 2/3 pyramidal neurons. The aberrant cortical function was also evident in awake animals by a reduced high frequency auditory steady-state responses (ASSR), reliably monitored by EEG. Importantly, the imbalance of excitatory to inhibitory function could be attenuated on a cellular and cortical network level by activation of mGlu2/3 receptors, indicating the relevance of excessive excitatory transmission to the cortical network deficit in the Df(15q13)/+ mouse model. Our findings highlight the preclinical value of genetic risk and in particular CNV models such as the Df(15q13)/+ mice to investigate pathological network correlates of schizophrenia risk and to probe therapeutic opportunities based on clinically relevant biomarkers.Competing Interest StatementThe authors have declared no competing interest.