Structural Plasticity in Neuropsychiatric Disorders

 

June 14 - 21, 2014

 

Coordinator: Eric J. Nestler

Mount Sinai School of Medicine, New York, USA

 

Faculty:

Michael Higley, Yale University, New Haven, USA

John Morrison, Mount Sinai School of Medicine, New York, USA

Dominique Muller, University of Geneva, Switzerland

Jochen Herms, Ludwig-Maximilians-University, Munich, Germany

Valentina Emiliani, Université Paris Descartes, France

David Lewis, University of Pittsburgh, USA

Hannah Monyer, University of Heidelberg, Germany

 

There has been increasing attention in recent years to structural plasticity of synapses in the brain. The molecular and cellular mechanisms controlling plasticity at presynaptic and postsynaptic elements is becoming more established and the importance of such plasticity—clearly related to altered function of excitatory and inhibitory synapses—is implicated in the regulation of normal brain function as well as in the diverse pathology seen in a range of neuropsychiatric conditions. The purpose of this Course is to review the highly sophisticated methodologies that are enabling an unprecedented evaluation of morphological regulation of synapses, and to discuss what this recent work is teaching us about the relationship between structural and functional plasticity of synapses, the molecular and cellular mechanisms underlying different forms of structural plasticity, and the contribution of such plasticity to normal and pathological brain function. John Morrison (Mount Sinai) will focus on plasticity at glutamatergic synapses in cerebral cortex during aging. Michael Higley (Yale) will discuss the influence of GABAergic signaling on synaptic plasticity. Dominique Muller (University of Geneva) will review the continual rewiring of brain circuits that occur through life as a consequence of structural plasticity at synapses. Jochen Herms (Munich Center for Neurosciences) will demonstrate the importance of morphological changes at synapses to the pathology of Alzheimer's disease. Eric Nestler (Mount Sinai) will discuss the molecular mechanisms by which stimulant drugs of abuse induce structural plasticity of excitatory synapses in striatal medium spiny neurons. Valentina Emiliani (Université Paris Descartes) will present new optogenetic and other optical tools that make it possible to precisely relate plasticity at specific microcircuits to regulation of behavioral outputs. Hannah Monyer (Heidelberg University) will review the important influence of GABAergic interneurons and projection neurons in the control of hippocampal and cortical circuits in the brain. Finally, David Lewis (University of Pittsburgh) will present evidence for the restructuring of excitatory and inhibitory circuits in prefrontal regions of cerebral cortex in schizophrenia.

 

John Morrison, Icahn School of Medicine at Mount Sinai, USA

Age-related alterations in cortical neurons, synapses, and neuronal plasticity: Implications for cognitive decline

The dorsolateral prefrontal cortex (dlPFC) in human and nonhuman primates controls a wide range of high-level cognitive processes by establishing and updating the contingencies for goal-directed behavior. Age-related cognitive decline is associated with the loss of a select class of highly plastic glutamatergic synapses in dorsolateral prefrontal cortex (PFC), whereas other classes of excitatory synapses are resistant to age-related changes. This suggests that the unique cognitive domains of prefrontal cortex require a high degree of synapse turnover and plasticity. In fact, the pattern of synaptic aging and the synaptic correlates of performance in hippocampus are quite different, suggesting that these two structures differ in their "synaptic strategy" for cognition as well as their vulnerability to aging. In addition, neurons and synapses in PFC appear to be highly responsive to endocrine effects of stress and sex steroids, as well as environmental conditions such as chronic stress, where these neurons undergo structural alterations that impact behaviors mediated by PFC. In fact, there is a convergence of endocrine and aging effects in the PFC, such that neurons within this region are protected by sex steroids such as estradiol, yet vulnerable to stress and both effects are age-dependent. The protective effects of estradiol suggest that while endocrine senescence may be linked to synaptic and cognitive aging, protection against age-related decline is feasible. In humans, protection of this class of spines/synapses may be a reasonable target for early intervention, prior to the degenerative cascade that results in extensive neuron death and the disastrous cognitive decline that occurs in Alzheimer's Disease.

 

Michael Higley, Yale University, USA

Inhibitory control of neuronal calcium signaling and synaptic plasticity

The precise balance of synaptic excitation and inhibition plays a critical role in normal brain function, and dysregulation of this balance is implicated in a number of neuropsychiatric disorders, including schizophrenia and autism. However, the cellular targets and consequences of GABAergic activity are still poorly understood. Recent studies have demonstrated that inhibitory synapses are potent regulators of dendritic calcium signaling. Ionotropic GABA-A receptors generate a powerful but local shunt that sculpts calcium transients in individual dendritic spines. Metabotropic GABA-B receptors limit the generation of widespread dendritic calcium spikes and modulate NMDA-type glutamate receptors. In keeping with these observations, a growing body of work indicates that inhibition strongly influences the strength and direction of calcium-dependent long-term synaptic plasticity. Thus, GABAergic signaling is likely to be a key determinant in the development and maintenance of neural circuits.

 

Dominique Muller, University of Geneva, CH

Structural plasticity of neurons in learning and memory

The concept of Hebbian plasticity based on changes in synaptic strength is central to our understanding of the mechanisms of learning and memory. However, accumulating evidence indicates that synaptic networks are also structurally plastic, and that connectivity is remodelled throughout life, through mechanisms of synapse formation, stabilization and elimination. These synaptic rearrangements occur in a spatially organized manner, they are regulated by neuronal activity and involve signaling pathways that partially overlap with those of synaptic plasticity. These structural rearrangements play an important role in mechanisms of circuit rewiring by providing specificity in the development of synaptic networks and new evidence suggests that alteration of these mechanisms could contribute to the pathogenesis of several developmental psychiatric disorders such as intellectual disability, autism spectrum disorders and schizophrenia.

 

Jochen Herms, Munich Center for Neurosciences, Germany

Using in vivo 2-photon imaging for the analysis of dendritic spine plasticity and pathology in mouse models of Alzheimer's and Parkinson's disease

Synaptic failure is believed to be one of the initial events in neurodegenerative diseases like Alzheimer's disease (AD) or Parkinson's disease (PD) and is supposed to be responsible for early clinical symptoms including alterations in olfaction or progressive dementia. In order to get more insights into how synapses are altered in these diseases we analyse the fate of individual synapses over weeks to months in transgenic mouse models by performing chronic in vivo two-photon imaging in brain regions which are easily accessible with this approach, such as the cerebral cortex or the olfactory bulb. We revealed that loss of spines and presynaptic terminals in the somatosensory cortex of AD transgenic mice does not occur prior to the formation of amyloid beta (Ab) plaques and is independent of the age of the experimental animals. Synaptic pathology can be attenuated with passive immunisation against Abeven though this does not affect the growth of amyloid plaques. However, other potential therapeutic options like inhibition of BACE1 or gamma secretase, enzymes which are critically involved in the production of Ab, were found to have significant negative effects on synaptic plasticity in wildtype mice. This indicates that the physiological functions of these proteins at the synapse have to be considered in explaining the lack of efficacy on cognition of those inhibitors in AD patients. In PD mouse models we analyse synapse and dendritic pathology by following the fate of adult-born neurons in the olfactory bulb. Here, olfactory dysfunction coincides with altered integration and maturation of adult-born granule cells and their dendro-dendritic synapses with mitral cells.


Eric Nestler, Icahn School of Medicine at Mount Sinai, USA

Molecular basis of structural plasticity of striatal medium spiny neurons to cocaine

Addictive drugs cause persistent restructuring of several neuronal cell types in the limbic regions of brain thought to be responsible for long-term behavioral plasticity that characterizes a state of addiction. These structural changes are best documented in nucleus accumbens medium spiny neurons (MSNs), and increasing evidence is available concerning the underlying molecular mechanisms driving this structural plasticity. Most information is available for cocaine and other psychostimulant drugs of abuse, which after chronic administration induce complex, time-dependent changes in MSN dendritic structure. At short time points after chronic drug exposure, there is an increase in the total number of dendritic spines on MSN neurons, an effect that represents primarily an increase in thin, immature spines and is associated with an induction of slient synapses. This effect predominates in D1-type MSNs, the MSN subtype which predominantly expresses the D1 dopamine receptor. At longer withdrawal time points, in contrast, D1-type MSNs display an increase in more mature, mushroom-shaped spines associated with enhanced glutamatergic transmission. We will review the role played by small GTPases and their downstream signaling cascades involving LIM-kinase and cofilin and a host of other actin-regulatory proteins in mediating these psychostimulant-induced changes in dendritic spine dynamics. We also will review the contribution of alterations in gene expression and chromatin mechanisms to this structural plasticity. Finally, we will define several major gaps in our knowledge and outline important steps for future research.

 

Valentina Emiliani, Neurophotonics Laboratory, France

Spatio temporal control of neuronal activity by wave front shaping and optogenetics

The combination of light microscopy and optogenetics offers the possibility to control activation and inhibition of neuronal activity enabling the analysis of well-defined neuronal population within intact neuronal circuits and systems. Interestingly, optogenetics has already permitted to address key biological questions with relatively simple illumination methods using widefield visible light illumination. However, some limitations in the specificity of genetic targeting and the intricate morphology of the brain make it challenging to, for example, individuate subsets of genetically identical interconnected cells, or to establish the role of specific spatiotemporal excitatory patterns in guiding animal behavior. To reach such degree of specificity, more sophisticated illumination methods are required. Here I will present a series of new optical methods recently developed in my laboratory for precise activation of optogenetics channels, based on wave front engineering of optical wave fronts. Exemplary experiments showing precise activation of ChR2, one of the most used optogenetic channels, in brain slices and in freely moving mice will be showed.

 

Hannah Monyer, Medical Faculty of Heidelberg University, Germany

GABAergic neurones control synchronous network activity and spatial coding in the hippocampal-entorhinal formation

GABAergic interneurons are crucially involved in the generation and maintenance of rhythmic synchronous activity in many forebrain regions, including the hippocampal-entorhinal formation. Genetic manipulations affecting the recruitment of GABAergic interneurons or abolishing the electrical coupling between GABAergic interneurons highlighted the functional role of GABAergic interneurons for spatial and/or temporal coding in the hippocampus. The genetic manipulations were always associated with distinct spatial memory deficits. To manipulate activity of selective neurons "online", we use optogenetics combined with in vivo recordings in freely moving mice. This allows the study of distinct interneurons, their connectivity with neighboring excitatory cells, as well as whether and how interneuron recruitment accounts for distinctive firing properties of spatially tuned cells. I will also present data demonstrating the presence of long-range GABAergic cells that connect the hippocampus and entorhinal cortex bi-directionally. By virtue of their connectivity – the target cells are most often local interneurons - this class of cells is ideally suited to synchronize brain regions over long distance. Finally I will present data demonstrating how neurogenesis of postnatally generated GABAergic interneurons is modulated.

 

David Lewis, University of Pittsburgh, USA

A neural substrate for impaired cortical network oscillations and cognitive dysfunction in schizophrenia

Deficits in cognitive control, the ability to adjust thoughts or behaviors in order to achieve goals, are now considered to be a core feature of schizophrenia and to be the best predictor of long-term functional outcome. Cognitive control depends on the coordinated activity of a number of brain regions, including the dorsolateral prefrontal cortex (DLPFC). Subjects with schizophrenia exhibit altered activation of the DLPFC, and reduced frontal lobe gamma band (~40 Hz) oscillations, when performing tasks that require cognitive control. Gamma oscillations require robust activity in the reciprocal connections between parvalbumin-containing basket cell class of cortical GABA neurons and neighboring pyramidal neurons. Thus, alterations in either the excitatory or inhibitory synapses in this circuit could contribute to impaired gamma oscillations and cognition in schizophrenia. This presentation will review the evidence for these types of alterations in the DLPFC of subjects with schizophrenia, and the convergent findings indicating which alterations are primary disturbances and which are compensatory responses. Together, the findings suggest a mechanistic model of "re-set" excitatory-inhibitory balance in DLPFC circuitry that both underlies the impaired gamma oscillations and accounts for the developmental course of functional disturbances in individuals with schizophrenia.