# Metabotropic glutamate receptor functions in autophagy

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2020 · $465,771

## Abstract

Abnormal maturation of brain circuitry during development is a critical determinant of pathological
manifestations in neuropsychiatric conditions including intellectual disability, Fragile X syndrome and
schizophrenia. A growing body of evidence from studies in human subjects and animal models has established
a link between dysfunctions in glutamatergic neurotransmission and developmental brain abnormalities
associated with these conditions. Group I metabotropic glutamate receptors, mGlu1 and mGlu5, are G protein-
coupled receptors critical to formation and maintenance of brain circuitry and synaptic plasticity, a cellular
substrate of learning and memory. Dysregulation of group I mGluR activity is implicated in neurodevelopmental
disorders including Fragile X syndrome and schizophrenia. The broad spectrum of deficits linked to group I
mGluR dysfunctions is not adequately explained by existing knowledge of receptor properties. We identified a
new mGlu1-interacting protein, fasciculation and elongation protein zeta-1 (FEZ1) encoded by a schizophrenia
candidate gene. Preliminary findings indicate that mGlu1 may function via FEZ1 to regulate autophagy in
neurons. Autophagy is an evolutionarily conserved catabolic process critical to neuronal homeostasis and brain
development. The proposed studies build on this progress to elucidate a fundamentally new mechanism by
which group I mGluRs can contribute to regulation of neuronal homeostasis under physiopathological
conditions.
 We propose to 1) determine the cellular mechanisms by which group I mGluRs regulate autophagy in
neurons; 2) define the molecular pathways by which the receptors control autophagy initiation; 3) establish
whether constitutively enhanced group I mGluR activity leads to autophagy impairment in an animal model of
Fragile X syndrome; and 4) investigate the function of autophagy in group I mGluR-dependent remodeling of
dendritic spines. Collectively, findings from these studies will significantly advance our understanding of the
molecular and cellular substrates underlying metabotropic functions in the brain and build a molecular
framework to understand cellular perturbations associated with synaptic pathologies in neurodevelopmental
disorders.

## Key facts

- **NIH application ID:** 9928499
- **Project number:** 5R01MH108614-06
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** ANNA FRANCESCONI
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $465,771
- **Award type:** 5
- **Project period:** 2016-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928499

## Citation

> US National Institutes of Health, RePORTER application 9928499, Metabotropic glutamate receptor functions in autophagy (5R01MH108614-06). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9928499. Licensed CC0.

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