Our research focus is the study of preclinical models of neurodevelopmental syndromes characterized by epilepsy and/or cognitive and behavioral deficits, which are currently without an approved therapy.
Furthermore, we investigate the impact of both physiological and environmental conditions, such as hormonal status and external stressors, on the phenotype, particularly on behavior. The goal is to understand how genetic risk factors and environmental inputs,including their interactions, influence the pathogenesis, symptomatology, and response to treatment, as well as to find new markers and targets for the identification of effective therapeutic strategies.
Our most current line of work focuses on the characterization and phenotyping of models of neurodevelopmental syndromes, such as the one carrying the GluN2A(N615S) mutation, which presents a high sensitivity to epileptic seizures, cognitive deficits and autistic-like behaviors, faithfully summarizing what happens in patients carrying similar mutations and affected by rare syndromes currently without effective treatments (Bertocchi et al., 2021; 2023). In particular, our recent work has demonstrated the high predictive value of our model, as the drug we have successfully tested on it is currently in use in an ongoing clinical trial in several European centers and is obtaining good results (Bertocchi et al., 2024).
A second model is that of Fragile X syndrome, which is the main monogenetic cause of autism. The goal of our study (among the Research Projects of Relevant National Interest 2023-25), is to identify specific brain areas and corresponding time windows of intervention that could be therapeutically relevant for new drug candidates.
OVER THE YEARS
One of the main lines of our research has been the study of the role of the neuropeptide Y (NPY) Y1 receptor (Y1R) in the limbic system. This contributed to a seminal publication that clarified the importance of NPY-Y1R signaling in maternal care mechanisms for the control of metabolism and emotional behavior (Bertocchi et al., 2011). We then provided, for the first time, experimental evidence that the major Y1 receptors co-expressed with Y5R are involved in the preservation of spatial memory (Longo et al., 2014) and are necessary for behavioral flexibility by regulating orbitofrontal cortex activity and serotonergic tone (Longo et al., 2018).
More recently, we demonstrated sex differences in the effects of limbic Npy1r inactivation and suggested the existence of an estrogen-dependent relay required for homeostasismaintenance, mediated by the hypothalamic Y1R receptor (Bertocchi et al., 2020; Eva et al., 2020). Furthermore, we contributed to highlighting a previously unknown functional link between NPY-Y1R transmission and perineuronal nets, extracellular matrix regulators of plasticity, which could play a role in the control of dorsal hippocampal excitability and related cognitive functions (Bertocchi et al., 2021).Finally, we demonstrated that female gonadal hormones and the hypothalamic NPY-Y1R system functionally interact in regulating neuroinflammation (Oberto et al., 2022).
A parallel line of research focuses on the role of glutamate receptors in synaptic plasticity and cognitive functions, thanks to international collaborations. Our laboratory has actively participated in the validation of genetic tools based on recombinant adeno-associated viruses (rAAV) for the inducible control of gene expression and the study of memory circuits. Using these advanced genetic tools, we have been able to provide new insights into associative memory in the motor cortex (Hasan et al., 2013) and into the role of the hypothalamic oxytocin system in memory extinction and glutamatergic transmission (Hasan et al., 2019).Our contribution was ultimately decisive in revealing that memories are formed through a consolidation mechanism that requires pre- and postsynaptic NMDA receptor signaling for the sequential printing of the memory engram from one brain region to another (Bertocchi et al., 2023). We then clarified the role of the dentate gyrus in memory retrieval and storage (Carretero-Guillén et al., 2024) and contributed to deciphering the role of different AMPA receptor subunits in spatial memory (Eltokhi et al., iScience 2023).
