Our laboratory is involved in two lines of research:
1. From microcircuits to behavior
The hippocampus is crucially involved in encoding contextual memory. Recently the relevance of the CA2 hippocampal sub-region for social memory, namely the capacity to remember a conspecific, has been highlighted. The goal of our research is to understand the mechanisms by which GABAergic and glutamatergic synaptic inputs contribute to this form of memory. This goal is achieved with combined in vivo electrophysiology behavioral and opto/chemogenetic tools to selectively manipulate the activity of GABAergic and glutamatergic pathways during social memory encoding. The modulatory effects of endogenously released acetylcholine, from neurons localized in the medial septum projecting to the hippocampus, on this form of memory is also assessed. Our final aim is to dissect the contribution of different components of the circuit involved in social memory encoding.
Cholinergic neurons expressing channelrhodhopsin (A) are activated by brief light pulses (blue dots) which reliably evokes action potentials (B). Scale bar: 20mm
2. Changes in microcircuit dynamics in Autism Spectrum Disorders
We aim at exploring the impact of trans-synaptic signaling underlying the formation of neuronal circuits in health and disease, in particular in Autism Spectrum Disorders (ASD).
ASD comprise a wide range of neuro-developmental disorders characterized by deficits in verbal and non-verbal communication, impaired social interactions, restricted interest, and stereotyped behavior. Among monogenetic forms of ASD, of particular interest are those related to single mutations of adhesion molecules of the neuroligin (NL) / neurexin (NRX) families.
NLs are postsynaptic proteins that by interacting with their presynaptic partners, neurexins, functionally couple the postsynaptic densities with the transmitter release machinery, thus contributing to synapses stabilization. Our model is a mouse strain carrying a single mutation (R451C) in the Nlgn 3 gene, found in patients affected by a non-syndromic form of Autism.
Using a variety of different approaches (from molecular biology and electrophysiology to imaging and behavior) we aim at elucidating how structural changes in synaptic adhesion molecules affect inhibitory and excitatory synaptic transmission within well-established hippocampal and cortical microcircuits, and their impact on rhythmogenesis, thought to be involved in high cognitive functions, with the final goal of identifying new targets for therapeutic intervention.
In collaboration with the group of A. Cattaneo, C. Marchetti and S. Marinelli, we aim at developing intrabodies able to selectively interfere with the NL/Nrx signaling in a NL isoform-specific manner.
Hippocampal pyramidal neuron transfected with HA-tagged-NL3R451C mutant and visualized with anti HA antibodies (red). Synaptic contacts are identified by apposition of the post-synaptic marker gephyrin (green) and the pre-synaptic marker VGAT (blue). Scale bar: 10mm
Lack of spike time-dependent potentiation (B,C) or depression (E, F) at mossy fiber-CA3 synapses in the hippocampus of NL3R451C knock-in mice as compared to littermate controls (A,C and D, F, respectively)