Cortical interneuron dynamics in the frontal and auditory cortices of
a mouse model of schizophrenia
Fhatarah A. Zinnamon1,2*, Sandra S. Wenas1*, Jennifer F. Linden1,3
2
1 Ear Institute, University College London
University College London (UCL) – National Institute of Mental Health (NIMH) Joint Doctoral Training Programme in Neuroscience
3 Department of Neuroscience, Physiology & Pharmacology, University College London
*These authors contributed equally to this work
Introduction
Results
22q11.2 Deletion Syndrome (22q11DS) is a genetic syndrome that results from a
1.5-3Mb congenital multigene deletion on the long arm of chromosome 22.
Approximately 25-30% of adults with 22q11DS develop schizophrenia during
adolescence or adulthood. As one of the most significant known cytogenetic risk
factors for schizophrenia, 22q11DS holds the potential to provide insight into neural
systems abnormalities associated with schizophrenia.
Of the 35 mice included in the study, 17 have been analysed.
Comparing results between Df1/+ and WT mice, we found significant reductions in
PV+ interneuron density in Df1/+ mice, especially in cortical layers III to VI of the
primary auditory cortex.
The Df1/+ mouse model of 22q11DS recapitulates many features of human 22q11DS
and schizophrenia, including cognitive impairment and frequent otitis media (OM), a
middle ear disease that can cause conductive hearing loss. In other model systems,
both hearing loss and schizophrenia risk factors have been shown to be associated
with abnormalities in parvalbumin-positive (PV+) inhibitory interneuron circuitry in the
cortex. However, the relationship between hearing loss, genetic risk of schizophrenia,
and PV+ interneuron circuitry remains poorly understood. We explored this relationship
by examining hearing loss and PV+ interneuron density in the auditory and frontal
cortices of Df1/+ mice.
Nissl staining in the auditory cortex PV+ staining in the auditory cortex Wt and Df1+ PV+ interneuron density
Numbers of PV+cells are significantly reduced in the auditory cortex of Df1/+ mice
Genetic risk factors of developing schizophrenia
Mouse chromosome 16 orthologous to human chromosome 22
Hypothesis
• An imbalance of excitation and inhibition in cortical circuits is thought to be the cause
of psychosis and cognitive dysfunction in schizophrenia [2-6].
• The influence of PV+ interneurons is reduced, causing patterns of activation within
cortical projection neurons to become more variable and less reliable in their patterns
of activation.
• Similar findings in fMRI and EEG studies in schizophrenic patients and normal
subjects with increased genetic risk of schizophrenia [7-9].
Methods
Auditory screening
• Previous work [1] has shown that about half of Df1/+ mice have conductive hearing
loss due to OM.
• We tested for OM or hearing loss in both left and right ears of 35 Df1/+ mice and their
WT littermates.
• Used tympanic membrane inspection and/or auditory brainstem response (ABR)
measurements.
Tympanic membrane inspection
ABR electrode placement and normal waveform
Immunohistochemistry & Imaging
• 50μm coronal sections
• Alternate slices for Nissl staining to identify frontal and auditory cortices
• PV+ interneuron density was quantified across
Conclusions
The results suggest that genetic risk of schizophrenia and developmental hearing loss
could interact to produce cumulative abnormalities in PV+ interneuron networks.
Current findings and the proposed work promise to provide insight into cortical
abnormalities associated with increased genetic risk of schizophrenia and will allow us
to assess the potential of the Df1/+ mouse as a model of cortical processing
abnormalities.
Nissl staining in the frontal cortex
PV+ staining in the frontal cortex
Wt and Df1+ PV+ interneuron density
No difference in number PV+cells in the prefrontal cortex between Df1/+ and WT mice
Future Directions
• Compare the performance of Df1/+ and WT mice on an auditory temporal
discrimination task.
• Using a two-alternative forced-choice behavioural training paradigm for mice, we
will analyze the performance of Df1/+ and WT mice on a task requiring
discrimination of fast and slow sound sequences.
• Identify differences between Df1/+ mice and their WT littermates in the response
properties of auditory cortical and/or frontal cortical neurons.
• Df1/+ mice and their WT littermates will receive single or dual chronic recording
array implants targeting core auditory cortical areas A1/AAF, or both auditory cortex
areas and the frontal cortex area M2.
• Neuronal responses to auditory stimuli will be recorded and the frequency
selectivity and temporal reliability of the neuronal responses to tones will be
analyzed.
• Compare correlations between auditory temporal discrimination behaviour and
temporal reliability of neuronal responses in Df1/+ and WT mice.
• The behavioural task involves using auditory information to guide a motor decision,
and is therefore likely to engage interactions between auditory and frontal cortices.
• Trained Df1/+ and WT mice will be implanted with electrode arrays in auditory
cortex and/or frontal cortex, so that neural activity can be recorded while the
animals perform the task.
• We will then determine how well behavioural performance of Df1/+ and WT mice
on the auditory temporal discrimination task correlates with temporal reliability of
neuronal responses in frontal and auditory cortex, and with coherence of neural
activity between the two areas.
• Further down the line, experiments involving optogenetic manipulation of interneuron
activity, in-vivo two-photon calcium imaging during the behavioural task, and measures
of sensorimotor gating will be pursued.
References
[1] Fuchs JC, Zinnamon FA, Taylor RR, Ivins S, Scambler PJ, Forge A, Tucker AS, Linden JF (2013) Hearing Loss in a Mouse Model of 22q11.2 Deletion
Syndrome. PLoS ONE 8(11): e80104.
[2] Marin O. (2012) Interneuron dysfunction in psychiatric disorders. Nat Rev Neurosci 13:107–120.
[3] Yizhar O, Fenno LE, Prigge M, Schneider F, Davidson TJ, O’Shea DJ, Sohal VS, Goshen I, Finkelstein J, Paz JT, Stehfest K, Fudim R, Ramakrishnan C,
Huguenard JR, Hegemann P, and Deisseroth K. (2011) Neocortical excitation/inhibition balance in information processing and social dysfunction. Nature,
477:171–178.
[4] Lewis DA, Hashimoto T, and Volk DW. (2005) Cortical inhibitory neurons and schizophrenia. Nat Rev Neurosci, 6:312–324.
[5] Loh M, Rolls ET and Deco G (2007). A dynamical systems hypothesis of schizophrenia. PLoS Computational Biology 3: 2255-2265.
[6] Winterer G and Weinberger DR (2004). Genes, dopamine and cortical signal-to-noise ratio in schizophrenia. Trends in Neurosciences 27: 683-690.
[7] Winterer G, Ziller M, Dorn H, Frick K, Mulert C, Wuebben Y, Herrmann WM, Coppola R (2000). Schizophrenia: reduced signal-to-noise ratio and impaired
phase-locking during information processing. Clinical Neurophysiology 111: 837-849.
[8] Winterer G, Coppola R, Goldberg TE, Egan MF, Jones DW, Sanchez CE and Weinberger DR (2004). Prefrontal broadband noise, working memory, and
genetic risk for schizophrenia. American Journal of Psychiatry 161: 490-500.
[9] Winterer G, Musso F, Beckmann C, Mattay V, Egan MF, Jones DW, Callicott JH, Coppola R and Weinberger DR (2006). Instability of prefrontal signal
processing in schizophrenia. American Journal of Psychiatry 163: 1960-1968.