Autism and the plas­tic brain

It’s all about com­mu­ni­ca­tion and con­nec­tiv­ity

The McGill Daily - - Sci+tech - Shane Wiebe Sci+tech Writer

Ac­cord­ing to the Cen­tre for Dis­ease Con­trol and Pre­ven­tion (CDC), an es­ti­mated one in 68 in­di­vid­u­als in the United States are cur­rently di­ag­nosed with Autism Spec­trum Dis­or­der (ASD); a preva­lence that has been ris­ing since the 1970s. Although the in­crease in num­bers is likely a pri­mary re­sult of broad­ened di­ag­nos­tic pa­ram­e­ters, these sta­tis­tics have been turn­ing heads in re­cent years and draw­ing the pub­lic’s at­ten­tion. Ac­cord­ingly, re­searchers have be­gun se­ri­ously con­sid­er­ing a long-stand­ing ques­tion: what is ASD and how does it oc­cur? To be clear, vac­cines, are not the cor­rect an­swer to the lat­ter.

ASD, col­lo­qui­ally known as Autism, is pri­mar­ily char­ac­ter­ized by dif­fi­cul­ties with so­cial in­ter­ac­tion, lack of ver­bal and non­ver­bal com­mu­ni­ca­tion, and repet­i­tive or re­stric­tive be­hav­ior, such as lin­ing up and or­der­ing ob­jects. In ad­di­tion to these core chal­lenges, in­di­vid­u­als may also present with al­tered learn­ing and mem­ory, epilepsy, ag­gres­sion, sleep dis­or­ders, anx­i­ety, and de­pres­sion. Be­cause it is a spec­trum dis­or­der, dif­fer­ent in­di­vid­u­als with ASD will ex­pe­ri­ence these prob­lems to a greater or lesser de­gree, which will dif­fer­en­tially af­fect their lives. As a con­se­quence, the jour­ney to un­der­stand and treat ASD is com­pli­cated and has his­tor­i­cally been mis­guided.

Up un­til the late 1960s, it was com­mon be­lief that Autism was due to a lack of ma­ter­nal af­fec­tion to­ward their child and the deroga­tory term “re­frig­er­a­tor moth­ers” was coined as a de­scrip­tion for the cause of the con­di­tion. This non-ev­i­dence-based la­bel un­doubt­edly caused dis­tress, and cer­tainly did not pro­vide suit­able grounds for thor­ough bio­med­i­cal in­ves­ti­ga­tion.

We now un­der­stand that the ge­netic makeup of an in­di­vid­ual, in com­bi­na­tion with cer­tain high-risk ge­netic mu­ta­tions, is para­mount for ASD eti­ol­ogy and sus­cep­ti­bil­ity. The prob­lem is that ASD is largely poly­ge­netic in na­ture, mean­ing it re­sults from al­ter­ations of mul­ti­ple genes in­volved in a va­ri­ety of func­tions. This makes study­ing ASD par­tic­u­larly chal­leng­ing and has ne­ces­si­tated the use of te­dious in­ves­tiga­tive par­a­digms.

The cur­rent strat­egy for un­der­stand­ing ASD im­ple­ments a ground up ap­proach. Sci­en­tists start with the iden­ti­fi­ca­tion of genes in­volved in the devel­op­ment of ASD, par­tic­u­larly in pa­tients with de novo mu­ta­tions com­pared with un­af­fected fam­ily mem­bers. With this in­for­ma­tion, sci­en­tists can un­der­stand how cer­tain mol­e­cules and pro­teins work in neu­ron to neu­ron com­mu­ni­ca­tion, how these con­nec­tions make func­tional cir­cuits in the brain, and how these cir­cuits func­tion in one or mul­ti­ple brain re­gions ul­ti­mately gov­ern­ing be­hav­ior.

We are start­ing to iden­tify clus­ters of genes in­volved in com­mon func­tions, thereby giv­ing us clues into the cel­lu­lar and molec­u­lar ba­sis of ASD. The reg­u­la­tory mech­a­nisms of pro­tein syn­the­sis and neu­ro­plas­tic­ity have be­come a ma­jor can­di­date in this re­gard.

MRNA trans­la­tion is the process by which new cel­lu­lar pro­teins are syn­the­sized based on the ge­netic code of an or­gan­ism. This is re­quired for cell growth and func­tion through­out the body, and main­tains phys­i­o­logic home­osta­sis. In the brain, pro­tein syn­the­sis is elab­o­rately reg­u­lated to en­sure ap­pro­pri­ate com­mu­ni­ca­tion between neu­rons and within neu­ral cir­cuits.

Con­nec­tions that are too strong or too weak can lead to aber­rant brain func­tion. Neu­ro­sci­en­tists are spec­u­lat­ing that this im­bal­ance between ex­ci­ta­tory and in­hibitory (E/I) neu­ral ac­tiv­ity is in­volved in ASD patho­gen­e­sis. Im­por­tantly, the So­nen­berg lab at Mcgill Univer­sity de­scribed how dys­reg­u­la­tion of the trans­la­tion ma­chin­ery re­sult­ing in en­hanced synap­tic pro­tein syn­the­sis leads to an Asd-like phe­no­type in mice. Can we, then, ther­a­peu­ti­cally tar­get reg­u­la­tory mech­a­nisms of trans­la­tion, cor­rect E/I im­bal­ance, and re­verse ASD patho­phys­i­ol­ogy? The an­swer is: maybe, but it’s not easy.

Cur­rent drug treat­ment op­tions for ASD are scarce and of­fer lit­tle sup­port for the core symp­toms. Un­for­tu­nately, since Autism is a spec­trum dis­or­der with a wide range of ge­netic het­ero­gene­ity, re­searchers are un­likely to find a ther­a­peu­tic for ev­ery ge­netic cause of ASD or to find one com­mon treat­ment for ev­ery case.

Fur­ther­more, the process of de­sign­ing ef­fec­tive neu­ro­log­i­cal med­i­ca­tion is com­pli­cated by poor drug de­liv­ery into the cen­tral ner­vous sys­tem (i.e. pen­e­tra­tion of the blood brain bar­rier), in ad­di­tion to off­tar­get ef­fects when it does en­ter the brain. Since neu­ral func­tion is fun- da­men­tally in­ter­con­nected, cor­rect­ing one prob­lem of­ten causes new com­pli­ca­tions to arise. In gen­eral, these chal­lenges have made the quest for dis­cov­er­ing ef­fec­tive neu­ro­logic phar­ma­ceu­ti­cals slow and frus­trat­ing.

The fu­ture of ASD re­search, how­ever, is more promis­ing. Sim­i­lar to the cur­rent strat­egy of tar­get­ing the trans­la­tion ma­chin­ery in can­cer, we may be able to use this ap­proach in the case of ASD.

Since trans­la­tion is reg­u­lated at many lev­els, there are likely drug­gable tar­gets that, when their func­tion is at­ten­u­ated or en­hanced, may cor­rect core deficits in ASD. This would in­deed, on a phys­i­o­log­i­cal level, ne­ces­si­tate pro­found rewiring of neu­ral cir­cuitry and re­shap­ing of cell-to-cell con­nec­tiv­ity. Is such a phe­nom­e­non even pos­si­ble? Should we even pur­sue such an end?

It was once thought that con­nec­tions between neu­rons are hard­wired and un­chang­ing but we now un­der­stand that they are flex­i­ble, plas­tic, and can change over time. Reg­u­lated pro­tein syn­the­sis is in­dis­pens­able for ap­pro­pri­ate neu­ro­plas­tic­ity. This abil­ity has con­sid­er­able im­pli­ca­tions for how mem­ory is stored in the brain, the way we learn to in­ter­act with our sur­round­ing en­vi­ron­ment, and ul­ti­mately how we ex­pe­ri­ence life. The is­sue is, then, how would chem­i­cally al­ter­ing neu­ral ac­tiv­ity with ther­a­peu­tics change that ex­pe­ri­ence? Fur­ther­more, can we cor­rect be­hav­ioral de- fects without al­ter­ing other as­pects of one’s life, such as their per­son­al­ity or even their mem­o­ries?

Even though our rel­a­tively plas­tic brains can be rewired, this does not nec­es­sar­ily mean that they should. ASD may be ex­pe­ri­enced as a real dis­or­der to some, but for oth­ers this may not be the case.

Steve Sil­ber­man, in his book about Autism and Neu­ro­di­ver­sity, states that “By autis­tic stan­dards, the “nor­mal” brain is eas­ily dis­tractible, is ob­ses­sively so­cial, and suf­fers from a deficit of at­ten­tion to de­tail and rou­tine. Thus, peo­ple on the spec­trum ex­pe­ri­ence the neu­rotyp­i­cal world as re­lent­lessly un­pre­dictable and chaotic, per­pet­u­ally turned up too loud, and full of peo­ple who have lit­tle re­spect for per­sonal space.” In part, the lack of un­der­stand­ing, on a per­sonal level, makes in­te­gra­tion into typ­i­cal so­ci­ety dif­fi­cult for some with ASD.

How­ever, the lack of un­der­stand­ing, on a sci­en­tific level, makes it nearly im­pos­si­ble to find real and ef­fec­tive so­lu­tions. In seek­ing to un­der­stand ASD, we are not only tak­ing steps for­ward to help those in need, but we are given the op­por­tu­nity to see into a new world from a new per­spec­tive. If we can com­mu­ni­cate, we can con­nect; if we can con­nect, we can un­der­stand; and if we can un­der­stand, we have a hope­ful fu­ture. I am talk­ing, of course, about the in­ner work­ings of Autism and the plas­tic brain.

Be­cause it is a spec­trum dis­or­der, dif­fer­ent in­di­vid­u­als with Autism Spec­trum Dis­or­der will ex­pe­ri­ence these prob­lems to a greater or lesser de­gree.

Rahma Wiry­omartono | The Mcgill Daily

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