SYNGAP1 Deficiency Alters the Pace of Neuronal Maturation

How do neuronal connections form and mature when a protein essential to regulating their function is deficient? This question was the focus of the doctoral thesis defended by Dr. Oriana Zerpa Rios on September 30. The research shows that SynGAP deficiency disrupts the coordination of neuronal development and identifies a potential new molecular signaling pathway to target to correct some of these alterations in experimental models.

The thesis, titled “CamKII dysregulation in SYNGAP1 deficiency: Connecting Developmental Alterations, Synaptic Signalling and Therapeutic Rescue,” was supervised by Dr. Àlex Bayés, from the Molecular Physiology of the Synapse group at the Sant Pau Research Institute (IR Sant Pau), and Dr. Nerea Roher Armentia, a full professor in the Department of Cell Biology, Physiology, and Immunology at the Universitat Autònoma de Barcelona.

The thesis examination committee consisted of Dr. Andrés Ozaita Mintegui, from the Universitat Pompeu Fabra, as chair; Dr. Xavier Altafaj Tardio, from the Universitat de Barcelona, as a member; and Dr. Laura Batlle Morera, from the Center for Genomic Regulation (CRG), as secretary.

SYNGAP1-related disorder has an estimated prevalence of one in 16,000 people and is one of the leading causes of intellectual disability caused by alterations in a single gene. It is also associated with epilepsy, autism spectrum disorder, and global developmental delay. The thesis investigates the mechanisms linking this genetic alteration to changes in neurons, with the aim of identifying potential therapeutic targets.

When Neuronal Structure and Function Develop at Different Rates

The SynGAP protein plays a key role in regulating synaptic activity. Among other functions, it controls the levels of AMPA-type receptors at the synapse, which mediate most excitatory transmission. The levels of these receptors largely determine synaptic strength and, ultimately, the mechanisms of synaptic plasticity underlying cognitive processes. 

Much of our knowledge of SynGAP comes from rodent models. However, differences between species in brain development and the pace of synaptic maturation make it difficult to study certain aspects of the human disorder. To address this limitation, the thesis used human neurons derived from embryonic stem cells, which were analyzed over seven weeks of differentiation.

Monitoring revealed that SynGAP-deficient neurons developed their extensions earlier and more rapidly and maintained more excitatory synapses. 

“We are not simply observing that SYNGAP1-deficient neurons develop faster, but that their structure and function develop at different rates,” explains Dr. Oriana Zerpa Rios.

The Role of CaMKII in Synaptic Alterations

The research also detected an accumulation of the CaMKIIα protein and its active form, which is involved in synaptic signaling. At the same time, researchers observed an alteration in the process that removes receptors from the membrane and brings them into the cell. At later stages, they also identified excessive activation of the Ras-ERK signaling pathway, which helps regulate neuronal development and function.

Taken together, these findings suggest that the accumulation of CaMKIIα at synapses could be one of the main mechanisms underlying the observed alterations. To explore this possibility, the study examined the effects of reducing its activity through a pharmacological intervention.

A Potential Target for Future Treatments

In human neurons, CaMKII inhibition normalized the synaptic alterations analyzed and corrected the excessive growth of neuronal extensions. The intervention was also evaluated in SynGAP-deficient mice, in which it corrected locomotor hyperactivity and deficits in spatial working memory, which allows information about the environment to be retained temporarily.

“CaMKII inhibition has allowed us to correct some alterations observed in human neurons and in mice. This gives us a basis for continuing to study this pathway as a potential therapeutic target, but we still need to determine whether these results can be translated to patients,” the researcher notes.