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Alteration Of Neuronal Excitability And Short-term Synaptic Plasticity In The Prefrontal Cortex Of A Mouse Model Of Mental Illness

Title: Alteration Of Neuronal Excitability And Short-term Synaptic Plasticity In The Prefrontal Cortex Of A Mouse Model Of Mental Illness.
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Name(s): Crabtree, Gregg W., author
Sun, Ziyi, author
Kvajo, Mirna, author
Broek, Jantine A. C., author
Fenelon, Karine, author
McKellar, Heather, author
Xiao, Lan, author
Xu, Bin, author
Bahn, Sabine, author
O'Donnell, James M., author
Gogos, Joseph A., author
Type of Resource: text
Genre: Journal Article
Text
Journal Article
Date Issued: 2017-04-12
Physical Form: computer
online resource
Extent: 1 online resource
Language(s): English
Abstract/Description: Using a genetic mouse model that faithfully recapitulates a DISC1 genetic alteration strongly associated with schizophrenia and other psychiatric disorders, we examined the impact of this mutation within the prefrontal cortex. Although cortical layering, cytoarchitecture, and proteome were found to be largely unaffected, electrophysiological examination of the mPFC revealed both neuronal hyperexcitability and alterations in short-term synaptic plasticity consistent with enhanced neurotransmitter release. Increased excitability of layer II/III pyramidal neurons was accompanied by consistent reductions in voltage-activated potassium currents near the action potential threshold as well as by enhanced recruitment of inputs arising from superficial layers to layer V. We further observed reductions in both the paired-pulse ratios and the enhanced short-term depression of layer V synapses arising from superficial layers consistent with enhanced neurotransmitter release at these synapses. Recordings from layer II/III pyramidal neurons revealed action potential widening that could account for enhanced neurotransmitter release. Significantly, we found that reduced functional expression of the voltagedependent potassium channel subunit K(v)1.1 substantially contributes to both the excitability and short-term plasticity alterations that we observed. The underlying dysregulation of K(v)1.1 expression was attributable to cAMP elevations in the PFC secondary to reduced phosphodiesterase 4 activity present in Disc1 deficiency and was rescued by pharmacological blockade of adenylate cyclase. Our results demonstrate a potentially devastating impact of Disc1 deficiency on neural circuit function, partly due to Kv1.1 dysregulation that leads to a dual dysfunction consisting of enhanced neuronal excitability and altered short-term synaptic plasticity.
Identifier: FSU_libsubv1_wos_000399440400015 (IID), 10.1523/JNEUROSCI.4345-15.2017 (DOI)
Keywords: schizophrenia, prefrontal cortex, cerebellar purkinje, Disc1 mouse model, excitability, false discovery rate, high-frequency oscillations, in-vitro, K-v channels, k+ channels, neocortical pyramidal neurons, pathological sharp waves, sensitive potassium channels, synaptic plasticity, temporal precision, vitro hippocampal slices
Publication Note: The publisher's version of record is available at https://doi.org/10.1523/JNEUROSCI.4345-15.2017
Persistent Link to This Record: http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000399440400015
Host Institution: FSU
Is Part Of: Journal of Neuroscience.
0270-6474
Issue: iss. 15, vol. 37

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Crabtree, G. W., Sun, Z., Kvajo, M., Broek, J. A. C., Fenelon, K., McKellar, H., … Gogos, J. A. (2017). Alteration Of Neuronal Excitability And Short-term Synaptic Plasticity In The Prefrontal Cortex Of A Mouse Model Of Mental Illness. Journal Of Neuroscience. Retrieved from http://purl.flvc.org/fsu/fd/FSU_libsubv1_wos_000399440400015