Substantial progress has been made toward understanding the genetic architecture, cellular substrates, brain circuits and endophenotypic profiles of neuropsychiatric disorders, including autism spectrum disorders (ASD), schizophrenia and Alzheimer's disease. Recent evidence implicates spiny synapses as important substrates of pathogenesis in these disorders. Although synaptic perturbations are not the only alterations relevant for these diseases, understanding the molecular underpinnings of spine pathology may provide insight into their etiologies and may reveal new drug targets. Here we discuss recent neuropathological, genetic, molecular and animal model studies that implicate structural alterations at spiny synapses in the pathogenesis of major neurological disorders, focusing on ASD, schizophrenia and Alzheimer's disease as representatives of these categories across different ages of onset. We stress the importance of reverse translation, collaborative and multidisciplinary approaches, and the study of the spatio-temporal roles of disease molecules in the context of synaptic regulatory pathways and neuronal circuits that underlie disease endophenotypes.

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Dendritic spine pathology in neuropsychiatric disorders

Abnormalities in functional connectivity between brain areas have been postulated as an important pathophysiological mechanism underlying schizophrenia. In particular, macroscopic measurements of brain activity in patients suggest that functional connectivity between the frontal and temporal lobes may be altered. However, it remains unclear whether such dysconnectivity relates to the aetiology of the illness, and how it is manifested in the activity of neural circuits. Because schizophrenia has a strong genetic component, animal models of genetic risk factors are likely to aid our understanding of the pathogenesis and pathophysiology of the disease. Here we study Df(16)A(+/-) mice, which model a microdeletion on human chromosome 22 (22q11.2) that constitutes one of the largest known genetic risk factors for schizophrenia. To examine functional connectivity in these mice, we measured the synchronization of neural activity between the hippocampus and the prefrontal cortex during the performance of a task requiring working memory, which is one of the cognitive functions disrupted in the disease. In wild-type mice, hippocampal-prefrontal synchrony increased during working memory performance, consistent with previous reports in rats. Df(16)A(+/-) mice, which are impaired in the acquisition of the task, showed drastically reduced synchrony, measured both by phase-locking of prefrontal cells to hippocampal theta oscillations and by coherence of prefrontal and hippocampal local field potentials. Furthermore, the magnitude of hippocampal-prefrontal coherence at the onset of training could be used to predict the time it took the Df(16)A(+/-) mice to learn the task and increased more slowly during task acquisition. These data suggest how the deficits in functional connectivity observed in patients with schizophrenia may be realized at the single-neuron level. Our findings further suggest that impaired long-range synchrony of neural activity is one consequence of the 22q11.2 deletion and may be a fundamental component of the pathophysiology underlying schizophrenia.

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Impaired hippocampal–prefrontal synchrony in a genetic mouse model of schizophrenia

Synaptic dysfunction is a key pathophysiological hallmark in several neurodegenerative disorders. In this Review, Lu and colleagues consider a 'synaptic repair'-based therapy for neurodegenerative diseases that targets pathophysiology rather than pathogenesis and discuss BDNF as a potential synaptic repair molecule.

BDNF-based synaptic repair as a disease-modifying strategy for neurodegenerative diseases

Protein palmitoylation, a classical and common lipid modification, regulates diverse aspects of neuronal protein trafficking and function. The reversible nature of palmitoylation provides a potential general mechanism for protein shuttling between intracellular compartments. The recent discovery of palmitoylating enzymes--a large DHHC (Asp-His-His-Cys) protein family--and the development of new proteomic and imaging methods have accelerated palmitoylation analysis. It is becoming clear that individual DHHC enzymes generate and maintain the specialized compartmentalization of substrates in polarized neurons. Here, we discuss the regulatory mechanisms for dynamic protein palmitoylation and the emerging roles of protein palmitoylation in various aspects of pathophysiology, including neuronal development and synaptic plasticity.

Protein palmitoylation in neuronal development and synaptic plasticity

Neurotrophins are growth factors with crucial roles in the developing and mature nervous system. They are initially synthesized as precursor proteins (pro-neurotrophins), which are processed intracellularly to be secreted mostly in a mature, biologically active form (Mowla et al., 1999; Mowla et al., 2001; Matsumoto et al., 2008; for review see Lu et al., 2005). Pro-neurotrophins can also influence developing and mature neural circuits, and may be released in a developmentally regulated manner (Lee et al., 2001; Lu et al., 2005; Teng et al., 2005; Yang et al., 2009). Neurotrophins bind two classes of membrane receptors, the tropomyosin receptor kinase (Trk) family of receptors and the p75 neurotrophin receptor (p75NTR) (for a review see Chao, 2003). The actions of mature neurotrophins are mediated by the high affinity full-length Trk receptors, which signal through their intrinsic tyrosine kinase activity to promote growth. Trk receptors signal by dimerization of receptor molecules, leading to intracellular phosphorylation and activation of intracellular signaling cascades (Ullrich and Schlessinger, 1990; Jing et al., 1992). Truncated Trk receptors (Trk.T) are splice variants of full-length Trks, which lack the intracellular tyrosine kinase domain, and are thought to act as negative effectors of full-length receptors (Luikart et al., 2003), although they may also have their own signaling properties (Rose et al., 2003; Ohira et al., 2006). The neurotrophins show binding specificity for particular Trk receptors: nerve growth factor (NGF) binds to TrkA, brain-derived neurotrophic factor (BDNF) and neurotrophin 4 (NT4) to TrkB, and neurotrophin 3 (NT3) to TrkC (Chao, 2003). The p75NTR has low affinity for the mature neurotrophins, but can form a complex with Trk receptors to form high affinity binding sites for neurotrophins, enabling the receptor to participate in the stimulation of growth processes (Esposito et al., 2001). Moreover, p75NTR displays high affinity binding with pro-neurotrophins, and induces apoptosis by interacting with sortilin (Lee et al., 2001; Nykjaer et al., 2004). Thus, pro-neurotrophins and mature neurotrophins may utilize distinct receptors to mediate divergent neuronal actions. This review focuses on the actions of mature BDNF, highlighting the role that BDNF plays in the development of synaptic connectivity in the central nervous system (CNS). Evidence supporting presynaptic actions by target-released BDNF, and the influence that BDNF exerts during the structural development of neurons are reviewed here.

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Brain-Derived Neurotrophic Factor and the Development of Structural Neuronal Connectivity

Individuals with 22q11.2 microdeletions have cognitive deficits and a high risk of developing schizophrenia. Here we provide evidence that primary hippocampal neurons from a mouse model of 22q11.2 deletion (Df(16)A(+/-) mice) have decreased density of dendritic spines and glutamatergic synapses, as well as impaired dendritic growth. These deficits were prevented by introduction of the enzymatically active ZDHHC8 palmitoyltransferase encoded by a gene in the 22q11.2 locus, and they were also observed in primary cultures from Zdhhc8-deficient mice. Many of these deficits were also present in the hippocampi of adult Df(16)A(+/-) and Zdhhc8-deficient mice. Finally, we provide evidence that PSD95 is one of the substrates of ZDHHC8. Our analysis reveals that 22q11.2 microdeletion results in deficits in neuronal development and suggests that impaired neuronal protein palmitoylation contributes to many of these deficits.

/pdf/palmitoylation-dependent-neurodevelopmental-deficits-in-a-9clsthske9.pdf

Luxiang Cao

Papers

Palmitoylation-dependent neurodevelopmental deficits in a mouse model of 22q11 microdeletion

Genetic Modulation of BDNF Signaling Affects the Outcome of Axonal Competition In Vivo