X-linked intellectual disability gene Oligophrenin-1 plays an important role in learning and memory

Nadif Kasri Nael

Mutations in the Oligophrenin-1 gene (OPHN1) cause intellectual disability, but the reasons why were still unknown. Nael Nadif Kasri Ph.D, molecular neurobiologist at the UMC St Radboud, presents his recent results on the cellular function of OPHN1 in the scientific journal "Neuron". OPHN1 appears to be indispensable for the weakening of synapses in neurons. Weakening of the synapses is an essential part of the processes that regulate how we learn, remember and forget. When this process is impaired this can lead to intellectual disability.  

What you want to learn you need to remember. This sounds simple, but what exactly happens in your brain when you learn or try to remember something? "At the cellular level learning is a biological process in which synapses - the tiny gaps across which nerve cells in the brain communicate - are being enhanced or weakened", says Nael Nadif Kasri, molecular neurobiologist at the UMC St Radboud. A synaptic connection becomes stronger when AMPA-type receptors are incorporated into the synapses and becomes weaker when AMPA-type receptors are removed from the synapse - what scientists respectively call long-term potentiation (LTP) and long-term depression (LTD).

Plasticity

Both, the increase (LTP) and the weakening (LTD) of the synapse are forms of synaptic plasticity. This synaptic plasticity is the cellular correlate of learning and memory. When you are unable to change the strength of the connections between neurons you cannot learn or forget. For the ability to learn synaptic plasticity is therefore essential. In Nijmegen Nadif Kasri investigates how synaptic plasticity is achieved at the molecular level. Which proteins are involved in these processes and what happens when one of these proteins does not function properly? In the past years he has investigated the function of OPHN1. Why? Nadif Kasri: "because since a few years it is known that mutations in the OPHN1 gene has a dramatic effect on the brain, causing X-linked intellectual disability". But what is really happening in the brain was still unknown.

Black box opened

In the online publication in Neuron Nadif Kasri and colleagues solved part of a puzzle concerning the relationship between the function of OPHN1 and changes in the strength of synapses. Nadif Kasri: '"we have pieced together essential steps in a signaling cascade within excitatory nerve cells that explains a key phenomenon called long-term depression, or LTD.  It was known that LTD starts with the activation of group I mGluRs and ultimately results in the retraction of AMPA-type receptors. However what is happening between the start and the end of this process was still a black box. We have now opened the black box. It was known that long-term depression mediated by mGluRs depended in part on the rapid synthesis of specific proteins. We have now shown that locally rapid production of OPHN1 protein follows activation of group I mGluRs.  OPHN1 in turn was shown to mediate LTD in hippocampal nerve cells, by interacting with yet another protein called EndophilinA2/3.  When rapid production of OPHN1 was blocked, mGluR-dependent LTD did not occur. " 

Fragile-X syndrome

When OPHN1 protein is absent or is not working properly, AMPA-type receptors stay at the synapse and a part of the synaptic plasticity is impaired. That is exactly what happens with mutations in OPHN1 that lead to intellectual disability. OPHN1 is one of the more than 400 genes that have been found causal to intellectual disability. Nadif Kasri: "we want to know the neuronal function of all the gene products of all those intellectual disability genes". This will allow us to gain fundamental insight in how learning and memory works and to make therapy more amenable in the near future. In that perspective the link with Fragile-X syndrome is interesting. 

Fragile-X syndrome is the most well-known and common form of intellectual disability. Fragile-X syndrome is caused by mutations in the FMR1 gene, which lies on the X-chromosome, just like the OPHN1 gene. Nadif Kasri:" Also the protein involved in Fragile-X plays a role in LTD. When mutated, LTD is overactive and too many AMPA-type receptors are removed from the synapse. This also results in the loss of synaptic plasticity and causes intellectual disability. Whereas a mutation in OPHN1 leads to too little AMPA-type receptor removal, a mutation in FMR1 leads to too much AMPA-type receptor removal.  In Fragile-X compounds are successfully being tested to block the effect of the mutation, those results look very promising. Although we are still far away from any therapy for OPHN1, we observe more and more parallels at the cellular level between genes and their gene products that are causing intellectual disability. The results on OPHN1 will therefore be very helpful in understanding the function of the other 400 genes involved in intellectual disability.

Rapid Synthesis of the X-Linked Mental Retardation Protein OPHN1 Mediates mGluR-Dependent LTD through Interaction with the Endocytic Machinery - Nael Nadif Kasri, Akiko Nakano-Kobayashi and Linda Van Aelst.

Online publicatie in Neuron

 

 


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