1. Genetic and cognitive windows into circuit mechanisms of psychiatric disease 
P. Alexander Arguello, Joseph A. Gogos 
Trends in Neurosciences 
Volume 35, Issue 1, Pages 3-13 (January 2012)
DOI: /j.tins
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2. Figure 1
Diversity of schizophrenia risk mutations scattered across the genome. The genetic etiology of schizophrenia is highly heterogeneous, as evidenced by recent studies of de novo mutations such as copy number variants (CNVs, stars) and point mutations (purple [2] and red circles [8]) identified in patients. As the pool of patients and controls increases, the list of potential rare disease-causing mutations is likely to grow as well. We only indicate de novo mutations for point of clarity and the fact they are more likely to be pathogenic. The de novo CNVs shown are those described in the literature as of July 2011 [9,30,113–116].
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3. Figure 2
Cognitive and synaptic plasticity phenotypes in selected mutant models of psychiatric, neurodegenerative and neurodevelopmental disorders. (a) Top, schematic of exemplar behavioral paradigms for assessing different forms of short-term (working) and long-term (reference) memory in rodents, as implemented with a T-maze and the Morris water maze (MWM), respectively. Middle and bottom panels, performance of schizophrenia mutant models in these tests. Middle, Df(16)A+/− mice, a model for the human 22q11 microdeletion associated with schizophrenia show deficits in acquiring a spatial working memory (WM) delayed-alternation task (left panel) [59], but display normal spatial reference memory in the MWM (right panel) [60]. Mice lacking a single copy of Dgcr8, a microRNA processor located within the deletion, also show similar WM deficits [59] (left panel). Bottom, mice carrying a truncating mutation in Disc1 associated with psychotic and affective disorders, Disc1tm1Kara, also show impairments in a WM delayed-alternation task [64] (left panel) and normal reference memory in the MWM [63] (right panel). (b) Top, schematic of anatomical locations, circuits and synapses where synaptic plasticity in the various mutant models was assessed. Middle, whole-cell recordings from deep layer 5 (L5) neurons of the medial prefrontal cortex (mPFC) show a greater degree of synaptic depression from superficial layer 2 (L2) inputs in 22q11-related mutant animals (left panel) and less post-tetanic potentiation (<45min) but normal long-term potentiation (LTP) (>45min, right panel) [81]. Bottom, field recordings from dentate gyrus (DG) mossy fiber inputs to CA3 of the hippocampus (HPC) show decreased frequency facilitation in Disc1 mutant mice (left and middle panels) but normal LTP at these same synapses (right panel) [60]. (c) Top, impaired performance of Alzheimer's model amyloid precursor protein/presenilin1 (APP/PS1) double transgenic mice in a spatial WM water maze task (left) and reference memory in the MWM (right) [67]. Bottom, performance of fragile X syndrome model Fmr1tm1Cgr knock-out mice in a spatial WM eight-arm radial maze task [117] (left) and impaired reference memory in a water maze task [118] (right). (d) Top, synaptic plasticity with conditional ablation of presenilins 1 and 2 (PS1/2) within CA3 of the HPC reveals reduced synaptic facilitation at CA3/CA1 synapses (left and middle panels) as well as theta-burst (TBS) induced LTP (right panel) [83]. Bottom, whole-cell recordings from CA1 cells show increased synaptic gain in Fmr1tm1Cgr mutants upon high-frequency stimulation of CA3 inputs [86] (left), and decreased LTP at medial perforant path entorhinal cortex (EC)/DG synapses [119] (right). Figures adapted, with permission, from [59,60,63,64] (a), [60,81] (b), [67,117,118] (c) and [83,86,119] (d).
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4. Figure 3
Long-range functional connectivity in a mouse model of the human 22q11.2 microdeletion. (a) Schematic of the brain regions electrophysiologically monitored while Df(16)A+/− mice performed a working memory (WM) task (left), and examples of traces of spikes (right) recorded in medial prefrontal cortex (mPFC) and local field potentials (LFPs) recorded in the dorsal hippocampus (HPC) [97]. (b) Phase-locking of mPFC neurons to HPC LFP during the memory (choice) and non-memory (sample) trials of the task was significantly reduced in mutant animals. (c) The time required for animals to learn the working memory task was significantly related to the degree of theta (θ, 4–10Hz) coherence between mPFC and HPC indicating that functional connectivity between these two structures facilitates the flow of spatial and mnemonic information needed to perform the task successfully. Figure panels (b) and (c) are adapted with permission from [97].
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5. Figure 4
Genetic strategy for identifying psychiatric disease circuits and mechanisms via cognitive assessment. Identifying disease-relevant circuits and mechanisms is made possible by a solid human genetics foundation. From bottom to top. A few disease mutations with robust associations with mental illnesses are selected for assessing their neurobiological impact in animal models. These mutant models recapitulate, as best as possible, the original disease-associated allele and undergo careful behavioral characterization. Ideally, to make disease-specific claims and discoveries, different mutant models from the same disease as well as different diseases are assessed. Advancing methods for cognitive testing allow different cognitive processes to be isolated and in turn implicate specific neural circuits and dynamics. The structure or function of these circuits can be disrupted across a broad spatiotemporal scale ranging from the local connections comprising microcircuits and distal connections comprising macrocircuits or even entire neural systems (left), and short and long-term forms of synaptic plasticity (right). Animal models of rare mutations associated with psychotic disorders such schizophrenia show more robust deficits in working memory rather than measures of episodic-like memory. They also show changes in various forms of short-term plasticity rather than long-term plasticity across different synapse types. Thus, mutant models from psychotic disorders in which information processing may be more affected than storage could show a relative bias towards more shorter forms of plasticity being affected (either increases or decreases in the magnitude of short-term plasticity, red traces) compared to models from more severe neurodevelopmental (purple) and neurodegenerative (green) disorders. Such effects could occur at either local circuit synapses and/or long-range connections (inset).
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