Brains process information and encode new stimuli through the activity of the underlying neuronal circuits, which in turn depend upon neuronal signaling and synaptic transmission. The balance between excitatory and inhibitory signals within these circuits is essential and its dysregulation has been linked to cognitive decline, psychiatric disorders and epilepsy. We seek to understand the mechanisms underlying these processes both in physiological and pathological conditions. To this end, we combine ex vivo electrophysiology with viral mediated gene transfer and behavior to study excitatory and inhibitory neuronal transmission in several brain areas, with a particular focus on the hippocampus and the dorsal raphe nuclei, two brain areas fundamental for processing of external stimuli.

The main lines of research of our laboratory are the following:

1. The interplay between microRNA, synaptic plasticity and the response to environmental stimuli

A key aspect of brain function is how environmental stimuli regulate synaptic function, and how in turn this influences the recruitment and adaptation of neuronal circuits. Central to this regulation is the role of microRNAs (miRNAs), small noncoding RNAs that modulate gene expression post-transcriptionally by controlling the translation and degradation of target messenger RNAs (mRNAs). miRNAs have highly specific expression patterns in the brain and their dysregulation has been implicated in disease states. We have recently shown that a particular miRNA, miR-34a, is specifically expressed in GABAergic neurons of the Dorsal Raphè Nuclei (DRN), the major source of serotonin in the brain. We also showed that it regulates inhibitory synaptic transmission onto serotoninergic neurons in response to specific environmental stimuli. In this context, our research aims at (a) elucidating the mechanisms through which this miRNA regulates synaptic plasticity, (b) what is the microcircuit recruited by this miRNA and (c) how its dysregulation might play a role in mood disorders. More generally, the long term goal is to gain further insight into how miRNAs shape the neuronal landscape to regulate the response to environmental challenges.

2. Role of neuroligins in neurodevelopmental disorders

Neuroligins are a family of postsynaptic cell adhesion molecules that regulate stabilization and function of both excitatory and inhibitory synapses. A number of neurodevelopmental disorders are associated to mutations in genes coding for these proteins. To better understand this link, we are currently investigating how loss of function of a particular neuroligin, neuroligin-2, impacts hippocampal neuronal transmission during development. At this stage, neuronal activity drives hippocampal circuit refinement, thereby influencing circuit wiring, long-term hippocampal function and susceptibility to epileptic seizures, possibly leading to increased neurodevelopmental learning delays.

3. Neuronal Excitability in Alzheimer’s Disease (AD)

While the most salient characteristics of AD is memory decline, electroencephalographic (EEG) recordings in brains of AD patients, people at high risk for AD, and of murine transgenic models have revealed altered electrical signaling well before the onset of cognitive decline, suggesting that modifications in neuronal electrical activity is detectable even at pre-symptomatic stages. We seek to understand what are the neuronal excitability properties that are altered in these early phases, how they relate to cognitive decline, and the underlying molecular mechanisms.

Selected Publications

Ielpo D, Guzzo SM, Porcheddu GF, Viscomi MT, Catale C, Reverte I, Cabib S, Cifani C, Antonucci G, Ventura R, Lo Iacono L, Marchetti C, Andolina D. GABAergic miR-34a regulates Dorsal Raphè inhibitory transmission in response to aversive, but not rewarding, stimuli. PNAS 2023 doi: 10.1073/pnas.2301730120

Rizzello E, Pimpinella D, Pignataro A, Titta G, Merenda E, Saviana M, Porcheddu GF, Paolantoni C, Malerba F, Giorgi C, Curia G, Middei S, Marchetti C. Lamotrigine rescues neuronal alterations and prevents seizure-induced memory decline in an Alzheimer’s disease mouse model. Neurobiol Dis. 2023 doi: 10.1016/j.nbd.2023.106106

Sgritta M, Vignoli B, Pimpinella D, Griguoli M, Santi S, Bialowas A, Wiera G,5 Zacchi P, Malerba F, Marchetti C, Canossa C, Cherubini E. Impaired synaptic plasticity in an animal model of autism exhibiting early hippocampal GABAergic-BDNF/TrkB signaling alterations. iScience 2023 doi: 10.1016/j.isci.2022.105728