Investigation of the Effect of Cannabidiol on PV+ Interneuron Maturation and the Response to Adolescent Stress: Potential Involvement of OTX2

• Grant number: 25/14274-2
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: December 01, 2025
• End date: April 30, 2029
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Francisco Silveira Guimaraes
• Grantee: João Raphael Campos Alves da Silveira
• Host Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated research grant: 23/16182-2 - Cannabidiol in the treatment of neuropsychiatric disorders: new paths, AP.TEM

Abstract

Adolescence is a critical period of neurodevelopment, characterized by heightened synaptic plasticity and remodeling of neural circuits. During this stage, regions such as the medial prefrontal cortex (mPFC) and the ventral hippocampus (vHip) undergo late maturational processes, making them particularly vulnerable to environmental insults. Epidemiological studies have shown that early-life stress contributes to the development of psychiatric disorders such as schizophrenia, depression, and anxiety. Moreover, preclinical data indicate that exposure to stress during this period is associated with long-lasting impairments, including cognitive deficits, reduced sociability, increased anxiety-related behaviors, and hyperactivity of hippocampal pyramidal neurons and dopaminergic neurons in the ventral tegmental area (VTA). These alterations are associated with impairments in GABAergic interneurons expressing parvalbumin (PVIs) and the surrounding perineuronal nets (PNNs). Proper maturation of PVIs and consolidation of PNNs are essential for the closure of critical periods of neurodevelopment, providing protection against environmental insults. In this context, the homeoprotein OTX2 is a key regulator of this process, being selectively internalized by PVIs via PNNs and promoting their maturation. The OTX2-PNN axis acts by regulating the onset and closure of plasticity across different brain regions. Thus, pharmacological interventions that modulate this axis may promote stress resilience and prevent associated alterations. Cannabidiol (CBD), a non-psychoactive constituent of Cannabis sativa, has demonstrated anxiolytic, antipsychotic, neuroprotective, and pro-plasticity effects, and is capable of modulating GABAergic neurotransmission and BDNF signaling. Data from our group and the literature indicate that CBD reverses alterations observed in animal models of schizophrenia and neurodevelopmental disorders, although the underlying mechanisms have not yet been fully elucidated. This project aims to investigate whether treatment with CBD during the prepubertal period can accelerate the maturation of PVIs and the formation of PNNs in the mPFC and vHip, thereby conferring protection against the effects of adolescent stress. Behavioral assessments will include anxiety-related, social, and cognitive parameters, alongside in vivo electrophysiological recordings of local field potentials (LFPs) in the vHip, mPFC, and VTA. Additionally, we will perform assays to quantify PV, PNNs, and OTX2 in the vHip and mPFC and explore the involvement of the OTX2-PNN axis through genetic manipulations aimed at overexpressing or silencing OTX2. The results will contribute to the understanding of the cellular mechanisms regulating stress vulnerability during neurodevelopment and the potential of CBD as a preventive strategy in risk contexts for psychiatric disorders. (AU)