mTOR-regulated autophagy and autism mouse models

I was intrigued to read the paper by Guomei Tang and colleagues [1] (open-access) and their assertion that: "mTOR [mammalian target of rapamycin]-regulated autophagy is required for developmental spine pruning, and activation of neuronal autophagy corrects synaptic pathology and social behavior deficits in ASD [autism spectrum disorder] models with hyperactivated mTOR".

"Re-verify our range to target... one ping only".

If that opening paragraph sounds like scientific gibberish, I'll refer you to one of the many media write-ups of the study (see here) describing how, among other things, researchers looked at brain tissue from the deceased with autism compared with those asymptomatic for autism and counted 'spines' (dendritic spines) - protrusions from a neuron. They reported "increased dendritic spine density with reduced developmental spine pruning in layer V pyramidal neurons in postmortem ASD temporal lobe". This is interpreted as "an oversupply of synapses" in certain parts of the brain and lead to headlines such as: "Scientists discover people with autism have too many brain 'connections'". All of this ties into the debates about brain connectivity in autism [2].

The next part of the Tang findings revolve around one of the possible 'whys' for their surplus of synapses findings talking about possible issues with the process of autophagy [3] - a sort of cellular housekeeping. The idea being that there are processes at work which clear out cells which we don't need or that are damaged including synaptic pruning. Here, the authors focused on something called mTOR (which has been previously discussed on this blog) specifically with it's link to autophagy [4]. Based on a mouse model of tuberous sclerosis (see here), a condition associated with autistic-like behaviour [5], researchers reported issues with mTOR activity which seemed to overlap with the findings of synaptic oversupply noted in brain samples from those with autism. Further "the medication rapamycin both restores normal synaptic pruning and reduces autism-like behaviors in a mouse model of autism" according to another commentary on the Tang study.

The NHS Choices website has already given the Tang study the once-over (see here) and noted: "this research is in its very early stages. It mainly helps our understanding of the brain changes that may be involved in this condition. It is too soon to say whether it could lead to any treatment for autism spectrum disorders, and even if it does it is likely to be a long way off". I'd echo those sentiments as well as adding a few of my own.

First, although no expert on the analysis of neural tissue, I note some more knowledgeable commentators have talked about how careful one has to be when drawing too many conclusions based on postmortem studies (see here). This also means taking into account the effect of any comorbidity that appeared alongside the diagnosis of autism and what role that might play in any results obtained. Second, is the reliance on a mouse model of autism (emphasis on 'mouse model') which, although overlapping with some autistic behaviours and with possibly related findings [6], is not necessarily representative of quite a lot of autism. Tuberous sclerosis for example, does seem to show some kind of relationship with autism [7] but as with other proposed less idiopathic types of autism (see here) one has to be a little bit careful in over-extrapolating any connection. Same goes for when one talks about increased spine density being found in all autism [8]. Finally, rapamycin is not exactly what one might call a desirable medication as a consequence of it's primary use and possible side-effects. I'm not saying that it doesn't have it's uses, just that when applied to real people with autism (not mouse models), the peer-reviewed literature is currently very, very sparse when it comes to efficacy and importantly safety. That being said, there may be other ways to inhibit mTOR [9] bearing in mind my caveat about not giving medical or clinical advice on this blog...

Music then. Rather Be...

----------

[1] Tang G. et al. Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits. Neuron. 2014. August 21.

[2] Uddin LQ. et al. Reconceptualizing functional brain connectivity in autism from a developmental perspective. Front Hum Neurosci. 2013 Aug 7;7:458.

[3] Glick D. et al. Autophagy: cellular and molecular mechanisms. J Pathol. 2010 May;221(1):3-12.

[4] Jung CH. et al. mTOR regulation of autophagy. FEBS Lett. 2010 Apr 2;584(7):1287-95.

[5] Reith RM. et al. Loss of Tsc2 in Purkinje cells is associated with autistic-like behavior in a mouse model of tuberous sclerosis complex. Neurobiol Dis. 2013 Mar;51:93-103.

[6] Isshiki M. et al. Enhanced synapse remodelling as a common phenotype in mouse models of autism. Nat Commun. 2014 Aug 21;5:4742.

[7] Smalley SL. Autism and tuberous sclerosis. J Autism Dev Disord. 1998 Oct;28(5):407-14.

[8] Wei H. et al. The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome. PLoS One. 2012;7(5):e36981.

[9] Theoharides TC. et al. Focal brain inflammation and autism. J Neuroinflammation. 2013 Apr 9;10:46.

----------

Tang, G., Gudsnuk, K., Kuo, S., Cotrina, M., Rosoklija, G., Sosunov, A., Sonders, M., Kanter, E., Castagna, C., Yamamoto, A., Yue, Z., Arancio, O., Peterson, B., Champagne, F., Dwork, A., Goldman, J., & Sulzer, D. (2014). Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits Neuron DOI: 10.1016/j.neuron.2014.07.040