Kyriaki Sidiropoulou, Ph.D.
Assistant Professor of Neurophysiology
Dept of Biology, Univ. of Crete
Collaborating Researcher
Institute of Molecular Biology and Biotechnology
Foundation for Research and Technology Hellas
Investigating the underlying mechanisms of neuropsychiatric disease
Investigating the underlying mechanisms leading to cognitive deficits in schizophrenia using animal models
Schizophrenia is the commonest and best known psychotic illness. Its symptoms are divided into 3 categories: 1) ‘positive symptoms’ include hallucinations, delusions and thought disorders, 2) ‘negative symptoms’ such as avolition and impaired social function, and 3) cognitive deficits including impairments in attention, executive function and working memory. The main brain areas affected in schizophrenia are the prefrontal cortex and hippocampus. One of the core deficits in the cortex of schizophrenic patients is the decrease in brain volume. Histologically, both schizophrenic patients and animal models of schizophrenia exhibit decrease in the volume of prefrontal cortex and hippocampus and a reduction in the levels of GABAergic inhibitory markers, such as the GAD-67 enzyme and the parvalbumin protein (Nakazawa et al. 2012).
While the etiology for schizophrenia is not completely understood, three main theories have developed to explain its emergence. These are:
1) the dopamine hypothesis
2) the NMDA receptor hypofunction hypothesis, and
3) the neurodevelopmental hypothesis
Based on the latter two hypotheses, our lab is establishing and investigating the underlying mechanisms that mediate the cognitive dysfunctions in two animal models of schizophrenia:
1) the neonatal MK-801, in which female pups receive a daily injection of the NMDA receptor antagonist between 11 and 15 postnatal days of age
2) the MAM model, pregnant mothers are treated with methylazoxymethanol acetate (MAM) at gestational day 16 or 17 and studies are performed in their offspring
Publications
K. Chalkiadaki, A. Velli, E. Kyriazidis, V. Stavroulaki, A. Chatzaki, M. Aivaliotis and K. Sidiropoulou (2018) Development of the MAM model of schizophrenia in mice: Sex similarities and differences in hippocampal and prefrontal cortical function, Neuropharmacology, 2018 Oct 23. pii: S0028-3908(18)30813-X. doi: 10.1016/j.neuropharm.2018.10.026. [Epub ahead of print]
Investigating the contribution of GABAergic interneurons to the development of neuropsychiatric diseases
Many neuropsychiatric disorders, such as epilepsy, anxiety, schizophrenia and autism exhibit an imbalance between excitatory and inhibitory mechanisms, in several brain regions including the PFC (Lewis et al., 2003; Yizhar et al., 2011; Marín, 2012). Specifically, reduction in interneuronal markers, such as GAD65/67 and PV, or GABA system adaptations have been correlated with several mental diseases, for example, schizophrenia (Lewis et al., 2003; Lodge et al., 2009; Hyde et al., 2011), autism (Fatemi et al., 2008a; 2008b; Blatt and Fatemi, 2011), depression (Markram et al., 2004; Kalueff and Nutt, 2007; Yizhar et al., 2011; Möhler, 2012) and epilepsy (Powell, 2013).
Although a reduction in GABAergic markers has been observed in several neuropsychiatric illnesses, it is not known whether these changes are causative or an adaptation of other primary modifications. The enhanced knowledge with regards to the transcription factors and intracellular mediators regulating various aspects of interneuron development has resulted in the generation of transgenic mouse lines with fewer cortical interneurons due to impaired proliferation and/or migration (Lewis et al., 2003; Cobos et al., 2005; Butt et al., 2008; Kerjan et al., 2009; Yizhar et al., 2011; Marín, 2012; Neves et al., 2012; Finlay and Uchiyama, 2015). These mice can be used to determine whether developmental defects in interneuron function would underlie network-wide changes in the brain.
In our lab, we utilize a transgenic mouse line that is missing the Rac1 gene from Nkx2.1/Cre-expressing cells (Rac1fl/fl/Nkx2.1 +/Cre) of the MGE (referred to as the Rac1 cKO mouse hereafter; (Vidaki et al., 2012)). This transgenic mouse was developed in the collaborating laboratory of Dr. Domna Karagogeos, at the Medical School, in the University of Crete. The Nkx1.2 transcription factor controls the generation of distinct interneuron subtypes originating from the MGE (Marin et al., 2000; Anderson et al., 2001). We have shown previously that the Rac1 cKO mice contain about 50% fewer MGE-derived GABAergic interneurons in the postnatal barrel cortex. This decrease results mainly from a longer G1 phase of MGE interneuron progenitors, leading to a delay in cell cycle exit, due to the Rac1 protein loss specifically from these cells (Vidaki et al., 2012). The interneurons found in the postnatal cortex have normal morphology, however the 50% that do not migrate remain aggregated in the ventral telencephalon and exhibit defective growth cones.
Using the Rac1 cKO mice, our goal is to determine how the developmental decrease in the number of interneurons affects the glutamatergic transmission properties of PFC neurons in adult mice. We demonstrate that PFC neurons of Rac1 cKO mice exhibit: a) decreased paired-pulse facilitation at 20Hz frequency, b) decreased LTP, c) reduced NR2A and NR2B subunits of the NMDA receptors, and d) reduced number of mushroom-type spines. In addition, we find that Rac1cKO mice treated with diazepam, a GABA-A receptor agonist, during the early postnatal period, do not develop the defect in dendritic morphology, suggesting that enhancement of GABA-A receptor function during that period reverses the detrimental effects of decreased number of interneurons in these mice.
In addition, we use computational modeling to investigate the contribution of the different types of cortical interneurons in network events, such as persistent activity. Persistent activity is regarded as the cellular correlate of working memory, a cognitive function affected in many neuropsychiatric disorders. We have used a cortical microcircuit model which includes pyramidal neurons and all the different subtypes of interneurons (fast-spiking, regular spiking and irregular spiking) in order to understand how the different properties of each interneuron subtype, such as firing or connectivity pattern, contribute to persistent activity characteristics. We find that somatic inhibition is critical for the emergence of persistent activity, however fast-spiking mediated inhibition control the firing rate of persistent activity.
Related publications
K. Kalemaki, X. Konstantoudaki, K. Sidiropoulou, and D. Karagogeos, Reduced threshold for epileptiform activity and differential responses to anti-epileptic drugs in mice with reduced number of interneurons, Frontiers in Neural Circuits, accepted