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Links between nutrition and the brain: how a maternal omega-3 deficiency can influence the behavioural development of offspring in animals

Animal and vegetable sources of omega-3 such as salmon, avocado, flax seeds, eggs, butter, nuts, almonds, pumpkin seeds, parsley leaves and colzal oil. © Fotolia

 

Omega-3 fatty acids* are essential, necessarily supplied by the diet and indispensable to brain development. Scientists from INRAE and University of Bordeaux, working in collaboration with INSERM, Laval and Toronto Universities in Canada and other partners (Harvard, Fondation Basque, etc.) have focused in particular on the impact of the maternal diet during gestation and lactation on the brain development of their offspring. They have thus shown for the first time in mice how an insufficient intake of omega-3 in the mother can alter the development of neuronal networks in the offspring, causing memory deficits. They have also deciphered the molecular mechanisms underpinning these effects. This unprecedented work, which is the result of several years of research, is published on 30 November 2020 in Nature Communications.

Essential fatty acids (omega 3 and 6) are massively incorporated in the brain of offspring via the maternal diet during gestation and lactation. Patchy scientific findings indicated that an insufficient consumption of these fatty acids by the mother during the perinatal period constitutes a risk factor for cognitive deficits in children (language, memory, learning, etc.). But what is the causal mechanism?

INRAE scientists from the Nouvelle-Aquitaine Research Centre and University of Bordeaux, and their colleagues, focused on a particular cell type in the brain: the microglial cells (or microglia) that participate in the shaping of the neuronal networks sustaining memory abilities. These brain macrophages lie at the interface between the environment and neurons.

During brain development, the microglia “sculpt” neuronal networks by “engulfing” useless synapses – the connectors between neurons – and only retaining those that are essential for satisfactory brain functioning.


The scientists focused their studies on a mouse model to determine whether maternal omega 3 status – and hence that of offspring – could exert an effect on microglia activity.

Omega 3 deficiency impacts the activity of a particular cell type in the mouse brain

The results showed for the first time that an insufficient intake of omega 3 via the maternal diet affects the activity of microglia in the developing brain; these cells adopt abnormal functioning and become hyperphagic; i.e. they lose the ability to recognise the synapses that needed to be deleted, hence “engulfing” too many of them. The neuronal network is thus poorly formed, causing deficits in the offspring memory capacities. The scientists were also able to decipher the molecular mechanisms responsible for this abnormal microglial activity.

To study this link between omega 3 intake and brain development, the scientists also developed several innovative technologies to evaluate the modification of microglial behaviour towards synapses, to analyse their lipid content, and to test different molecules in order to identify those responsible for this dysfunction and determine how it could be restored.

This work offers new perspectives for research, and studies will continue in humans in order to better understand the links between omega 3 and brain development.

In the general population, many pregnant women are deficient in omega 3, and the early identification of individuals at risk could enable preventive measures in order to counterbalance this deficiency.

* Omega 3 fatty acids are a family of essential fatty acids. This contains the fatty acids that are essential to developing satisfactory functioning of the body, but they can only be supplied by diet. They are found in numerous vegetable oils (walnut, rapeseed, linseed, etc.) and in the flesh of fatty fish.

A new cerebral canalopathy associating intellectual disability and abnormal movements

Brain scan, X-ray © Fotolia

 

Dysfunctions of ion channels – or channelopathies – in the brain are today associated with more than 30 neurological diseases such as epilepsy or cerebellar ataxias. Structures located on the membrane of cells allowing the passage of ions (for example sodium and potassium ions) between the interior of a cell and its external environment (extracellular environment), these channels make it possible in particular to generate and control d potentials. action in neurons. A study conducted at the Brain Institute (Sorbonne University / Inserm / AP-HP / CNRS) identified a new cerebral channelopathy originating from dominant mutations in the KCNN2 gene, encoding the SK2 ion channel. The results were published in Brain on November 27, 2020.

 

Pathogenic variants of the KCNN2 gene identified in patients and their location on the protein structure of the SK2 channel.

The variants in red are pathogenic variants truncating (introducing a stop codon into the protein sequence). Variants in black are pathogenic missense variants associated with loss of function. The variant in gray was classified of unknown significance because the channel with this variant did not show any particular deficit in electrophysiology.

 

Dr Fanny Mochel, geneticist in the genetics department of the Pitié-Salpêtrière hospital AP-HP and researcher at the Brain Institute (Sorbonne University / Inserm / AP-HP / CNRS) and Professor Christel Depienne, A geneticist at the Institute of Human Genetics at the University Hospital of Essen (Germany) and also a researcher at the Brain Institute have identified a new syndrome associated with mutations in the SK2 channel. The study published in the scientific journal Brainconcerns 10 patients, 6 men and 4 women aged 2 to 60 years with more or less severe intellectual delays associated, for some, with autism spectrum disorders or psychotic episodes. These cognitive disorders are in all cases associated with tremors, symptoms of cerebellar ataxia or even abnormal movements.

Thanks to a collaboration with Agnes Rastetter from the genotyping / sequencing platform of the Brain Institute (Sorbonne University / Inserm / AP-HP / CNRS), the genome of a first patient recruited at Pitié-Salpêtrière was analyzed at the search for genetic mutations at the origin of this syndrome. This analysis revealed a mutation in the KCNN2 gene interrupting its coding sequence, absent from the patient’s parents ( de novo mutation ). Brain imaging by MRI (magnetic resonance imaging) in this patient showed abnormalities in the structure and integrity of the white matter of the brain, that is, the cerebral sheath that protects the axons of neurons.

In addition, an international collaboration has enabled researchers to identify 9 other patients with mutations in the KCNN2 gene . The majority of these mutations had arisen de novo while a mutation was transmitted in a familial form of the same syndrome.

Finally, by working jointly with Carine Dalle from the electrophysiology cell exploration platform of the Brain Institute, the teams of Dr Mochel and Depienne have shown a deleterious role of these mutations on the function of the SK2 channel, i.e. that is to say a loss of function leading to a dysfunction of the ion channel SK2 and therefore a loss of regulation of the action potential, support of the nervous message.

The results of this new study have identified a new cerebral channelopathy originating from dominant mutations in the KCNN2 gene , encoding the SK2 ion channel. This new syndrome is characterized by the presence, on the one hand, of cognitive symptoms, in particular an intellectual disability, and, on the other hand, of motor symptoms such as abnormal movements.

This new pathology, the cause of which is now known, is very heterogeneous from a point of view of symptoms and requires multidisciplinary management at the border between genetics, for the search for mutations in the KCNN2 gene, pediatric neurology and neurology. for the management of cognitive and motor manifestations of patients.

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