Emergence of synaptic organization and computation in dendrites

Abstract Single neurons in the brain exhibit astounding computational capabilities, which gradually emerge throughout development and enable them to become integrated into complex neural circuits. These capabilities derive in part from the precise arrangement of synaptic inputs on the neurons’ dendrites. While the full computational benefits of this arrangement are still unknown, a picture emerges in which synapses organize according to their functional properties across multiple spatial scales. In particular, on the local scale (tens of microns), excitatory synaptic inputs tend to form clusters according to their functional similarity, whereas on the scale of individual dendrites or the entire tree, synaptic inputs exhibit dendritic maps where excitatory synapse function varies smoothly with location on the tree. The development of this organization is supported by inhibitory synapses, which are carefully interleaved with excitatory synapses and can flexibly modulate activity and plasticity of excitatory synapses. Here, we summarize recent experimental and theoretical research on the developmental emergence of this synaptic organization and its impact on neural computations.

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Reply to reviewers: Reuse, embodied interactivity, and the emerging paradigm shift in the human neurosciences

Behavioral and Brain Sciences ◽

10.1017/s0140525x15001703 ◽

2016 ◽

Vol 39 ◽

Author(s):

Michael L. Anderson

Keyword(s):

Evolutionary Psychology ◽

Functional Diversity ◽

Paradigm Shift ◽

Evolutionary Biology ◽

Spatial Scales ◽

Future Research ◽

Cognitive Sciences ◽

Multiple Spatial Scales ◽

Neural Reuse ◽

The Brain

AbstractIn this reply to reviewers, I argue that, although reforming the taxonomy of psychology will lead to great insights in the cognitive sciences, it will not result in 1:1 structure-function mappings in the brain; we should expect to see a great deal of irreducible functional diversity in the brain at multiple spatial scales. I further clarify both the promise and the limitations of the analytic techniques for capturing functional diversity and interrogating the taxonomy of psychology; describe the ways in which neural reuse can help us understand human development; further explore the ways in which my proposals for integrating psychology, neuroscience, and evolutionary biology differ from the approach exemplified by contemporary evolutionary psychology; and lay out some new and hopefully interesting avenues for future research.

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AUTS2 regulation of synapses for proper synaptic inputs and social communication

10.1101/871012 ◽

2019 ◽

Cited By ~ 1

Author(s):

Kei Hori ◽

Kunihiko Yamashiro ◽

Taku Nagai ◽

Wei Shan ◽

Saki F. Egusa ◽

...

Keyword(s):

Psychiatric Disorders ◽

Social Communication ◽

Neuronal Migration ◽

Vocal Communication ◽

Excitatory Synapses ◽

Synaptic Inputs ◽

Electrophysiological Recordings ◽

Fos Expression ◽

The Brain ◽

Primary Cultured Neurons

AbstractImpairments in synapse development are thought to cause numerous psychiatric disorders. Autism susceptibility candidate 2 (AUTS2) gene has been associated with various psychiatric disorders, such as autism and intellectual disabilities. Although roles for AUTS2 in neuronal migration and neuritogenesis have been reported, its involvement in synapse regulation remains unclear. In this study, we found that excitatory synapses were specifically increased in the Auts2-deficient primary cultured neurons as well as Auts2 mutant forebrains. Electrophysiological recordings and immunostaining showed increases in excitatory synaptic inputs as well as c-fos expression in Auts2 mutant brains, suggesting that an altered balance of excitatory and inhibitory inputs enhances brain excitability. Auts2 mutant mice exhibited autistic-like behaviors including impairments in social interaction and altered vocal communication. Together, these findings suggest that AUTS2 regulates excitatory synapse number to coordinate E/I balance in the brain, whose impairment may underlie the pathology of psychiatric disorders in individuals with AUTS2 mutations.

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Associative Learning and Motivation Differentially Requires Neuroligin-1 at Excitatory Synapses

10.1101/2020.01.01.890798 ◽

2020 ◽

Cited By ~ 1

Author(s):

Jiaqi Luo ◽

Jessica M Tan ◽

Jess Nithianantharajah

Keyword(s):

Decision Making ◽

Brain Connectivity ◽

Excitatory Synapses ◽

Response Effort ◽

Trade Off ◽

Signaling Complex ◽

Neural Computations ◽

Decision Making Processes ◽

And Behavior ◽

The Brain

ABSTRACTIn a changing environment, a challenge for the brain is to flexibly guide adaptive behavior towards survival. Understanding how these decision-making processes and underlying neural computations are orchestrated by the structural components of the brain, from circuits to cells, and ultimately the signaling complex of proteins at synapses, is central to elucidating the mechanisms that shape normal and abnormal brain connectivity, plasticity and behavior. At excitatory synapses, neuroligin-1 (Nlgn1) a postsynaptic cell-adhesion molecule required for the formation of trans-synaptic complexes with presynaptic partners is critical for regulating synapse specification, function and plasticity. Extensive evidence shows Nlgn1 is essential for synaptic transmission and long-term plasticity, but how these signaling processes ultimately regulate components of cognitive behavior is much less understood. Here, employing a comprehensive battery of touchscreen-based cognitive assays, we measured two key decision problems: i) the ability to learn and exploit the associative structure of the environment and ii) the trade-off between potential rewards and costs, or positive and negative utilities associated with available actions. We found that mice lacking Nlgn1 have an intact capacity to acquire complex associative structures and adjust learned associations. However, loss of Nlgn1 alters motivation leading to a reduced willingness to overcome response effort for reward and an increased willingness to exert effort to escape an aversive situation. We suggest Nlgn1 may be important for balancing the weighting on positive and negative utilities in reward-cost trade-off. Our findings identify Nlgn1 is essential for regulating distinct cognitive processes underlying decision-making, providing evidence of a new model for dissociating the computations underlying learning and motivational processing.

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Regulation of Hippocampal Excitatory Synapses by the Zdhhc5 Palmitoyl Acyl Transferase

10.1101/2020.09.11.294397 ◽

2020 ◽

Author(s):

Jordan J. Shimell ◽

Andrea Globa ◽

Marja D. Sepers ◽

Angela R. Wild ◽

Nusrat Matin ◽

...

Keyword(s):

Inhibitory Synapses ◽

Excitatory Synapses ◽

Silent Synapses ◽

Synapse Plasticity ◽

Hippocampal Synapses ◽

The Brain ◽

Spine Number

ABSTRACTPalmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5’s enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

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Multi-spatial scale dynamic interactions between functional sources reveal sex-specific changes in schizophrenia

Network Neuroscience ◽

10.1162/netn_a_00196 ◽

2021 ◽

pp. 1-48

Author(s):

A. Iraji ◽

A. Faghiri ◽

Z. Fu ◽

S. Rachakonda ◽

P. Kochunov ◽

...

Keyword(s):

Spatial Scale ◽

Spatial Scales ◽

Dynamic State ◽

Model Order Selection ◽

Dynamic Interactions ◽

Model Order ◽

Functional Interactions ◽

Multiple Spatial Scales ◽

Temporal Domain ◽

The Brain

Abstract We introduce an extension of independent component analysis (ICA), called multiscale ICA (msICA), and design an approach to capture dynamic functional source interactions within and between multiple spatial scales. msICA estimates functional sources at multiple spatial scales without imposing direct constraints on the size of functional sources, overcomes the limitation of using fixed anatomical locations, and eliminates the need for model-order selection in ICA analysis. We leveraged this approach to study sex-specific and -common connectivity patterns in schizophrenia. Results show dynamic reconfiguration and interaction within and between multi-spatial scales. Sex specific differences occur (1) within the subcortical domain, (2) between the somatomotor and cerebellum domains, and (3) between the temporal domain and several others, including the subcortical, visual, and default mode domains. Most of the sex-specific differences belong to between-spatial scale functional interactions and are associated with a dynamic state with strong functional interactions between the visual, somatomotor, and temporal domains and their anticorrelation patterns with the rest of the brain. We observed significant correlations between multi-spatial scale functional interactions and symptom scores,highlighting the importance of multiscale analyses to identify potential biomarkers for schizophrenia. As such, we recommend such analyses as an important option for future functional connectivity studies.

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Regulation of hippocampal excitatory synapses by the Zdhhc5 palmitoyl acyl transferase

Journal of Cell Science ◽

10.1242/jcs.254276 ◽

2021 ◽

Author(s):

Jordan J. Shimell ◽

Andrea Globa ◽

Marja D. Sepers ◽

Angela R. Wild ◽

Nusrat Matin ◽

...

Keyword(s):

Inhibitory Synapses ◽

Excitatory Synapses ◽

Silent Synapses ◽

Synapse Plasticity ◽

Hippocampal Synapses ◽

The Brain ◽

Spine Number

Palmitoylation is the most common post-translational lipid modification in the brain; however, the role of palmitoylation and palmitoylating enzymes in the nervous system remains elusive. One of these enzymes, Zdhhc5, has previously been shown to regulate synapse plasticity. Here, we report that Zdhhc5 is also essential for the formation of excitatory, but not inhibitory synapses both in vitro and in vivo. We demonstrate in vitro that this is dependent on Zdhhc5's enzymatic activity, its localization at the plasma membrane, and its C-terminal domain which has been shown to be truncated in a patient with schizophrenia. Loss of Zdhhc5 in mice results in a decrease in the density of excitatory hippocampal synapses accompanied by alterations in membrane capacitance and synaptic currents, consistent with an overall decrease in spine number and silent synapses. These findings reveal an important role for Zdhhc5 in the formation and/or maintenance of excitatory synapses.

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Calsyntenin-3 directly interacts with neurexins to orchestrate excitatory synapse development in the hippocampus

10.1101/2020.01.24.918722 ◽

2020 ◽

Author(s):

Hyeonho Kim ◽

Dongwook Kim ◽

Jinhu Kim ◽

Hee-Yoon Lee ◽

Dongseok Park ◽

...

Keyword(s):

Neural Circuits ◽

Conditional Knockout ◽

Excitatory Synapse ◽

Stratum Radiatum ◽

Excitatory Synapses ◽

Synapse Development ◽

Ca1 Neurons ◽

Synaptic Inputs ◽

Presynaptic Differentiation

AbstractCalsyntenin-3 (Clstn3) is a postsynaptic adhesion molecule that induces presynaptic differentiation via presynaptic neurexins (Nrxns), but whether Nrxns directly bind to Clstn3 has been a matter of debate. Here, we show that β-Nrxns directly interact via their LNS domain with Clstn3 and Clstn3 cadherin domains. Expression of splice site 4 (SS4) insert-positive β-Nrxn variants, but not insert-negative variants, reversed the impaired Clstn3 synaptogenic activity observed in Nrxn-deficient neurons. Consistently, Clstn3 selectively formed complexes with SS4-positive Nrxns in vivo. Neuron-specific Clstn3 deletion caused significant reductions in number of excitatory synaptic inputs, and moderate impairment of light-induced anxiety-like behaviors in mice. Moreover, expression of Clstn3 cadherin domains in CA1 neurons of Clstn3 conditional knockout mice rescued structural deficits in excitatory synapses, especially within the stratum radiatum layer. Collectively, our results suggest that Clstn3 links to SS4-positive Nrxns to induce presynaptic differentiation and orchestrate excitatory synapse development in specific hippocampal neural circuits.

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Multi-Spatial Scale Dynamic Interactions between Functional Sources Reveal Sex-Specific Changes in Schizophrenia

10.1101/2021.01.04.425222 ◽

2021 ◽

Author(s):

A. Iraji ◽

A. Faghiri ◽

Z. Fu ◽

S. Rachakonda ◽

P. Kochunov ◽

...

Keyword(s):

Spatial Scale ◽

Spatial Scales ◽

Dynamic State ◽

Model Order Selection ◽

Dynamic Interactions ◽

Model Order ◽

Functional Interactions ◽

Multiple Spatial Scales ◽

Temporal Domain ◽

The Brain

AbstractWe introduce an extension of independent component analysis (ICA), called multiscale ICA (msICA), and design an approach to capture dynamic functional source interactions within and between multiple spatial scales. msICA estimates functional sources at multiple spatial scales without imposing direct constraints on the size of functional sources, overcomes the limitation of using fixed anatomical locations, and eliminates the need for model-order selection in ICA analysis. We leveraged this approach to study sex-specific and -common connectivity patterns in schizophrenia.Results show dynamic reconfiguration and interaction within and between multi-spatial scales. Sex-specific differences occur (1) within the subcortical domain, (2) between the somatomotor and cerebellum domains, and (3) between the temporal domain and several others, including the subcortical, visual, and default mode domains. Most of the sex-specific differences belong to between-spatial scale functional interactions and are associated with a dynamic state with strong functional interactions between the visual, somatomotor, and temporal domains and their anticorrelation patterns with the rest of the brain. We observed significant correlations between multi-spatial-scale functional interactions and symptom scores, highlighting the importance of multiscale analyses to identify potential biomarkers for schizophrenia. As such, we recommend such analyses as an important option for future functional connectivity studies.

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Synaptic organization of the gustatory NST

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100168487 ◽

1994 ◽

Vol 52 ◽

pp. 150-151

Author(s):

M. C. Whitehead

Keyword(s):

Central Nervous System ◽

Dendritic Spines ◽

Fundamental Problem ◽

Cell Types ◽

Brain Regions ◽

Excitatory Synapses ◽

Solitary Tract ◽

Synaptic Organization ◽

Synaptic Junctions ◽

Afferent Terminals

A fundamental problem in taste research is to determine how gustatory signals are processed and disseminated in the mammalian central nervous system. An important first step toward understanding information processing is the identification of cell types in the nucleus of the solitary tract (NST) and their synaptic relationships with oral primary afferent terminals. Facial and glossopharyngeal (LIX) terminals in the hamster were labelled with HRP, examined with EM, and characterized as containing moderate concentrations of medium-sized round vesicles, and engaging in asymmetrical synaptic junctions. Ultrastructurally the endings resemble excitatory synapses in other brain regions.Labelled facial afferent endings in the RC subdivision synapse almost exclusively with distal dendrites and dendritic spines of NST cells. Most synaptic relationships between the facial synapses and the dendrites are simple. However, 40% of facial endings engage in complex synaptic relationships within glomeruli containing unlabelled axon endings particularly ones termed "SP" endings. SP endings are densely packed with small, pleomorphic vesicles and synapse with both the facial endings and their postsynaptic dendrites by means of nearly symmetrical junctions.

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