Electrophysiological and proteomic characterization of engram neurons and the role of CDC37 during memory formation

• Grant number: 24/22231-9
• Support Opportunities: Scholarships abroad - Research Internship - Doctorate (Direct)
• Start date: May 01, 2025
• End date: April 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: Alexander Henning Ulrich
• Grantee: Guilherme de Araujo Juvenal
• Supervisor: Baufreton Jerome
• Host Institution: Instituto de Química (IQ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: Université de Bordeaux, Carreire/Victoire, France
• Associated to the scholarship: 22/10950-5 - Selection and evaluation of proteins and fundamental mechanisms for the formation of long-term memory, BP.DD

Abstract

Human memory is a complex higher-order cognitive process responsible for classifying, encoding, storing, and retrieving information. Protein synthesis in the hippocampus and the interaction dynamic between them are essential for forming long-term memory (LTM). Our previous findings suggest that the interaction dynamics of cell division cycle protein 37 (CDC37) with STX1A, LRRK2, and THAP7 may play a role in LTM. CDC37 is a co-chaperone that recruits client protein to heat shock protein 90 (HSP90). We investigated whether the HSP90/CDC37 interaction, and the subsequent dissociation of the complex with target proteins STX1A, THAP7, or LRRK2, impairs memory. To evaluate this hypothesis, we disrupted the HSP90/CDC37 complex using celastrol and specifically inhibited CDC37 activity with 4,5,6,7-tetrabromobenzotriazole (TBB). We observed that celastrol treatment in the SAMP8 mouse model of premature aging and dementia enhances memory acquisition, as demonstrated by fear conditioning and passive avoidance tests. These findings suggest the critical role of CDC37 interactions in memory processes. We aim to investigate the correlation between this co-chaperone interaction and engram neurons regarding memory formation. We will employ the Tet-tag system to label engram neurons and use in vivo optogenetic stimulation to activate them. We will also characterize the electrophysiological properties and proteomic profile of labeled engram neurons to identify potential mechanisms of the engramming process and the role of the CDC37 protein.