Mosaic synapses in epilepsy

doi:10.1126/science.abh3555

GSTDTAP > 气候变化

DOI	10.1126/science.abh3555
	Mosaic synapses in epilepsy
	Belal Shohayeb; Helen M. Cooper
	2021-04-16
发表期刊	Science
出版年	2021
英文摘要	The inherited X-linked early-onset childhood epilepsy, called EFMR (epilepsy and mental retardation limited to females), has baffled clinicians and geneticists for more than 50 years. In contrast to other X-linked disorders in which the hemizygous (hemi) male, but not the heterozygous (het) female is affected, it is only the het females that exhibit seizures and intellectual disability ([ 1 ][1], [ 2 ][2]). Clues to the origin of this enigmatic disorder came when deleterious mutations in the X chromosome gene protocadherin-19 ( PCDH19 ), which encodes a cell adhesion molecule, were identified ([ 3 ][3]). On page 255 of this issue, Hoshina et al. ([ 4 ][4]) provide answers to two pieces of the EFMR puzzle: They reveal that hippocampal synaptic transmission is compromised in Pcdh19 het female mice but not in hemi males, and they provide a molecular explanation for how the retention of one wild-type (WT) allele, but not the loss of both alleles, disrupts neuronal connectivity. In general, females with X-linked disorders are asymptomatic because they carry one WT allele. Conversely, hemi males only express the mutated gene and are unable to produce a functional protein. What accounts for the EFMR sex reversal? Important insight came with the identification of idiopathic males with EFMR symptoms ([ 5 ][5]). Affected males carried postzygotic somatic PCDH19 mutations, and therefore regions within the developing brain that normally express PCDH19 comprise a mixture of PCDH19-positive and -negative (has a nonfunctional PCDH19 allele) neurons. To ensure appropriate levels of gene expression, females undergo X-inactivation in which one X chromosome is silenced. Females heterozygous for PCDH19 mutations will therefore also exhibit somatic mosaicism due to random X-inactivation in individual cells. This raises the question of how the coexistence of PCDH19-positive and -negative neurons might perturb brain development. In EFMR, seizures begin at ∼10 months of age and dissipate in adolescence ([ 1 ][1], [ 2 ][2]). PCDH19 is expressed in the developing hippocampus and neocortex, brain regions associated with higher-order functions such as cognition and memory, and is highly expressed when synapses are forming after birth. However, its role in the establishment of neuronal circuitry remains poorly understood. Hoshina et al. focused on the hippocampal mossy-fiber pathway, which plays a central role in memory and mood regulation and has been implicated in some epilepsies ([ 6 ][6], [ 7 ][7]). In this pathway, the excitatory dentate granule cells receive input from the entorhinal cortex and form mossy-fiber synapses on CA3 pyramidal neurons. Hoshina et al. found a reduction in the size of the presynaptic compartment as well as a depletion in synaptic vesicles in Pcdh19 het female mice but not hemi males or WT females. The CA3 postsynaptic compartment as well as mossy-fiber axon targeting and synaptic density were not affected in het females. These data suggest that the presence of PCDH19 on only one side of the synaptic cleft may directly affect presynaptic function. Electrophysiological recordings confirmed that the efficiency of neurotransmitter release was compromised in het females. Moreover, the induction of long-term potentiation (LTP), an electrophysiological correlate of presynaptic function and thus memory formation, was completely abolished at the het synapse. The authors also found that het females displayed clear behavioral deficits that were consistent with mossy synapse dysfunction, unlike WT females and hemi males. These findings strongly suggest that the existence of PCDH19 mosaic synapses has detrimental consequences for presynaptic development and thus hippocampal function. How does this PCDH19 synaptic mismatch perturb mossy-fiber synapses? To explain the unusual mode of inheritance for EFMR, the “cellular interference” hypothesis has been proposed and emerges from the homophilic adhesive binding properties of the protocadherins ([ 1 ][1], [ 5 ][5]). This model postulates that in mosaic individuals, PCDH19-positive cells are unable to establish adhesive interactions with PCDH19-negative cells, disrupting tissue cohesion. In hemi males, however, cell-cell adhesion is restored because of the compensatory activity of other protocadherin family members. ![Figure][8] Synaptic mosaicism Deleterious mutations in the X-chromosome gene protocadherin-19 ( PCDH19 ) cause epilepsy and mental retardation limited to females (EFMR). In female mice, loss of PCDH19 function (negative PCDH19) in some cells, but not others (mosaicism), leads to mismatched synapses. It is proposed that N-cadherin homophilic adhesion is prohibited between PCDH19-positive and -negative neurons, which prevents presynaptic development. GRAPHIC: V.ALTOUNIAN/ SCIENCE Armed with this information, Hoshina et al. tested the validity of this hypothesis in the context of the mossy-fiber synapse. Homophilic binding of the classical cadherin N-cadherin promotes adhesion between the pre- and postsynaptic membranes to initiate synapse formation ([ 8 ][9]). Moreover, N-cadherin forms cis heterodimers with PCDH19 ([ 9 ][10]). The authors therefore suspected that PCDH19–N-cadherin heterodimer mismatches may underpin synapse dysfunction. They showed that N-cadherin colocalized with PCDH19 in 80% of WT female mossy-fiber synapses but only in 40% of het female synapses and never in hemi males. In parallel, recruitment of β-catenin (a downstream effector of N-cadherin) to the N-cadherin cytodomain was significantly reduced only in het synapses. N-cadherin–β-catenin interactions were therefore retained when PCDH19 was lost from both the pre- and postsynaptic membrane or, conversely, when it was present on both membranes. Further studies showed that increasing the level of N-cadherin expression at mismatched synapses restored presynaptic development and LTP induction. The authors propose a plausible mismatch model to explain how PCDH19 mosaicism at the mossy-fiber synapse elicits cognitive deficits in EFMR individuals (see the figure). In WT females, trans-synaptic signaling through homophilic adhesion between PCDH19–N-cadherin heterodimers on opposing membranes promotes β-catenin–mediated presynaptic signaling and development. In hemi males, N-cadherin homophilic adhesion is still permitted when PCDH19 is completely absent, triggering β-catenin signaling. In the mosaic synapse, however, N-cadherin homophilic adhesion is prohibited between PCDH19-positive and -negative compartments, leading to compromised presynaptic development and cognitive impairment. Given that many members of the protocadherin family are involved in cell-cell recognition during brain development ([ 10 ][11]), this raises the question of whether protocadherin–N-cadherin trans-adhesion is a general mechanism for ensuring that the correct pre- and postsynaptic partners initiate synapse formation. One perplexing aspect of this study is that Pcdh19 het female mice do not exhibit seizures. The dentate granule neurons are excitatory, and their hyperactivity contributes to some epilepsies ([ 6 ][6], [ 11 ][12]). Paradoxically, the study of Hoshina et al. shows that PCDH19 synaptic mismatch leads to reduced synaptic activity. So, does PCDH19 synaptic mismatch initiate or propagate epileptogenic activity? In humans, the mossy-fiber pathway is embedded in complex neuronal circuitry that imposes finely tuned excitatory and inhibitory regulation on granular cell activity and downstream neuronal networks ([ 6 ][6], [ 11 ][12]). 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领域	气候变化 ; 资源环境
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文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/322883
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Belal Shohayeb,Helen M. Cooper. Mosaic synapses in epilepsy[J]. Science,2021.
APA	Belal Shohayeb,&Helen M. Cooper.(2021).Mosaic synapses in epilepsy.Science.
MLA	Belal Shohayeb,et al."Mosaic synapses in epilepsy".Science (2021).