A new study from Fleming researchers published in Journal of Neuroscience shows that excess GABAergic signaling impairs associative learning in Neurofibromatosis type 1.
Neurofibromatosis Type 1 (NF1) is an autosomal, dominant, multisymptomatic and characteristically clinically variable disorder. NF1 is the result of mutations in Neurofibromin (Nf1), a regulatory protein of multiple cellular processes, including Ras inactivation and activation of adenylyl cyclase.
Cognitive dysfunction is among the hallmark symptoms of NF1, and accordingly, loss of the Drosophila melanogaster ortholog of Neurofibromin (dNf1) precipitates associative learning deficits. However, the affected circuitry in the adult central nervous system remained unclear and the compromised mechanisms debatable. Although the main evolutionarily conserved function attributed to Nf1 is to inactivate Ras, decreased cAMP signaling on Nf1 loss has been thought to underlie impaired learning.
The study performed by Skoulakis Lab, entitled “Associative learning requires Neurofibromin to modulate GABAergic inputs to Drosophila mushroom bodies” revealed that dNf1 loss results in excess GABAergic signaling to the central for associative learning mushroom body (MB) neurons, apparently suppressing learning. Significantly, the study demonstrated that dNf1 is necessary and sufficient for learning within these non-MB GABAergic neurons, as an anaplastic lymphoma kinase (dAlk)- and Ras1-dependent, but cAMP/PKA-independent modulator of GABAergic neurotransmission.
Georganta EM, Moressis A, Skoulakis EMC. (2021) “Associative learning requires Neurofibromin to modulate GABAergic inputs to Drosophila mushroom bodies”, J Neurosci 41(24):5274-5286. doi: 10.1523/JNEUROSCI.1605-20.2021.
PMID: 33972401
Pubmed link: https://pubmed.ncbi.nlm.nih.gov/33972401/