Impact of typical antipsychotic on parvalbumin-positive interneurons and perineuronal nets: motor and cognitive effects

• Grant number: 25/07600-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: October 01, 2025
• End date: March 31, 2027
• Field of knowledge: Biological Sciences - Pharmacology - Neuropsychopharmacology
• Principal Investigator: Elaine Aparecida Del Bel Belluz Guimarães
• Grantee: Rafaela Aparecida Ponciano da Silva de Moraes
• Host Institution: Faculdade de Odontologia de Ribeirão Preto (FORP). 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

Parvalbumin-positive GABAergic interneurons (PVI+) form essential inhibitory microcircuits that maintain neuronal activity balance. These interneurons are sorrounded by perineuronal nets (PNNs), specialized extracellular matrix structures that contribute to synaptic stability and neural plasticity. Alterations in PVI+ and PNNs have been implicated in the pathophysiology of disorders such as schizophrenia, particularly due to NMDA receptor hypofunction in PVI+, leading to glutamatergic and dopaminergic imbalances. Typical antipsychotics, such as haloperidol, are used to treat positive symptoms of schizophrenia but can cause tardive dyskinesia (TD) with chronic use. TD is characterized by involuntary orofacial movements, known as vacuous chewing movements (VCMs) in animal models, and may be accompanied by cognitive deficits. Pre-existing factors associated with schizophrenia may increase vulnerability to treatment, complicating the translation of animal models to humans. Moreover, schizophrenia-related brain alterations might predispose individuals to TD independently of antipsychotic use. ¿Combining schizophrenia and TD models is crucial for investigating TD's pathophysiological mechanisms and the involvement of PVI+ and PNNs. Cannabidiol (CBD) has demonstrated neuroprotective and antidyskinetic properties, including attenuation of PV+ alterations induced by the NMDA antagonist MK-801. This study will employ a combined schizophrenia and TD model (MK-801 treatment followed by haloperidol) to examine how changes in PVI+ and PNNs influence VCMs and cognitive deficits. Additionally, we will assess whether CBD treatment can reverse these alterations. Behavioral, pharmacological, and histological approaches will be used, focusing on key regions such as the prefrontal cortex, motor cortex, dorsolateral striatum, and dorsal hippocampus, to elucidate the cellular and therapeutic mechanisms involved in TD and the potential role of CBD in modulating PVI+ and PNNs.¿ (AU)