Why we need more synaptogenic cell-adhesion proteins

Brose, Nils

doi:10.1073/pnas.1300505110

Cited by 7 publications

(4 citation statements)

References 10 publications

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“…At present, precisely how Slitrks promote distinct types of synapse development in an isoform-dependent manner remains to be elucidated ( Yim et al, 2013 ), but it would be worthwhile investigating the relationship between altered synapse numbers induced by Slitrk missense mutations and the development of associated neuropsychiatric disorders in follow-up studies. Intriguingly, Slitrk family proteins resemble neuroligin family proteins in many ways ( Brose, 2013 ). For example, the action of Slitrk3 at inhibitory synapses is phenomenologically analogous to that of neuroligin-2, whereas the effects of the other Slitrk family members are related to those of neuroligin-1.…”

Section: Discussionmentioning

confidence: 99%

Slitrk Missense Mutations Associated with Neuropsychiatric Disorders Distinctively Impair Slitrk Trafficking and Synapse Formation

Kang

Han

Won

et al. 2016

Front. Mol. Neurosci.

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Slit- and Trk-like (Slitrks) are a six-member family of synapse organizers that control excitatory and inhibitory synapse formation by forming trans-synaptic adhesions with LAR receptor protein tyrosine phosphatases (PTPs). Intriguingly, genetic mutations of Slitrks have been associated with a multitude of neuropsychiatric disorders. However, nothing is known about the neuronal and synaptic consequences of these mutations. Here, we report the structural and functional effects on synapses of various rare de novo mutations identified in patients with schizophrenia or Tourette syndrome. A number of single amino acid substitutions in Slitrk1 (N400I or T418S) or Slitrk4 (V206I or I578V) reduced their surface expression levels. These substitutions impaired glycosylation of Slitrks expressed in HEK293T cells, caused retention of Slitrks in the endoplasmic reticulum and cis-Golgi compartment in COS-7 cells and neurons, and abolished Slitrk binding to PTPδ. Furthermore, these substitutions eliminated the synapse-inducing activity of Slitrks, abolishing their functional effects on synapse density in cultured neurons. Strikingly, a valine-to-methionine mutation in Slitrk2 (V89M) compromised synapse formation activity in cultured neuron, without affecting surface transport, expression, or synapse-inducing activity in coculture assays. Similar deleterious effects were observed upon introduction of the corresponding valine-to-methionine mutation into Slitrk1 (V85M), suggesting that this conserved valine residue plays a key role in maintaining the synaptic functions of Slitrks. Collectively, these data indicate that inactivation of distinct cellular mechanisms caused by specific Slitrk dysfunctions may underlie Slitrk-associated neuropsychiatric disorders in humans, and provide a robust cellular readout for the development of knowledge-based therapies.

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Section: Discussionmentioning

confidence: 99%

Slitrk Missense Mutations Associated with Neuropsychiatric Disorders Distinctively Impair Slitrk Trafficking and Synapse Formation

Kang

Han

Won

et al. 2016

Front. Mol. Neurosci.

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“…Interestingly, despite these few instances, constitutive or conditional knock-out (KO) models for the vast majority of SAMs do not exhibit any large-scale impairments in synapse formation and only affect their functional maturation, which occasionally might lead to a subsequent loss of synapses over time 11 – 15 . Furthermore, SAM-dependent mechanisms are yet to explain the productions of different types of synapses, because several postsynaptic SAMs specifically localized at either glutamatergic or γ-aminobutyric acid (GABA) -ergic principal synapses can often interact with common presynaptic binding partners that are similarly distributed at both synapse types 16 – 18 . Hence, alternative cellular signals other than SAMs could be either primarily or simultaneously required for synaptogenesis and reliable alignment of complementary synaptic apparatus.…”

Section: Introductionmentioning

confidence: 99%

Induction of synapse formation by de novo neurotransmitter synthesis

et al. 2022

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A vital question in neuroscience is how neurons align their postsynaptic structures with presynaptic release sites. Although synaptic adhesion proteins are known to contribute in this process, the role of neurotransmitters remains unclear. Here we inquire whether de novo biosynthesis and vesicular release of a noncanonical transmitter can facilitate the assembly of its corresponding postsynapses. We demonstrate that, in both stem cell-derived human neurons as well as in vivo mouse neurons of purely glutamatergic identity, ectopic expression of GABA-synthesis enzymes and vesicular transporters is sufficient to both produce GABA from ambient glutamate and transmit it from presynaptic terminals. This enables efficient accumulation and consistent activation of postsynaptic GABAA receptors, and generates fully functional GABAergic synapses that operate in parallel but independently of their glutamatergic counterparts. These findings suggest that presynaptic release of a neurotransmitter itself can signal the organization of relevant postsynaptic apparatus, which could be directly modified to reprogram the synapse identity of neurons.

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“…First, multiple synaptic adhesion proteins appear to operate in concert or even in parallel and redundantly, rather than individually, to control synapse formation and define synapse-specific functional features [5,6]. Accordingly, obtaining detailed insights into the mechanism of specific synapse and circuit formation from analyses of individual adhesion proteins or even of entire protein families has proven challenging.…”

Section: Introductionmentioning

confidence: 99%

Synapse biology in the ‘circuit-age’—paths toward molecular connectomics

Schreiner

Savas

Herzog

et al. 2017

Current Opinion in Neurobiology

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The neural connectome is a critical determinant of brain function. Circuits of precisely wired neurons, and the features of transmission at the synapses connecting them, are thought to dictate information processing in the brain. While recent technological advances now allow to define the anatomical and functional neural connectome at unprecedented resolution, the elucidation of the molecular mechanisms that establish the precise patterns of connectivity and the functional characteristics of synapses has remained challenging. Here, we describe the power and limitations of genetic approaches in the analysis of mechanisms that control synaptic connectivity and function, and discuss how recent methodological developments in proteomics might be used to elucidate the molecular synaptic connectome that is at the basis of the neural connectome.

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Why we need more synaptogenic cell-adhesion proteins

Cited by 7 publications

References 10 publications

Slitrk Missense Mutations Associated with Neuropsychiatric Disorders Distinctively Impair Slitrk Trafficking and Synapse Formation

Slitrk Missense Mutations Associated with Neuropsychiatric Disorders Distinctively Impair Slitrk Trafficking and Synapse Formation

Induction of synapse formation by de novo neurotransmitter synthesis

Synapse biology in the ‘circuit-age’—paths toward molecular connectomics

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