# Mechanisms of Synaptic Homeostasis Governing Pre-Sympathetic Neurons in the Hypothalamic Paraventricular Nucleus

> **NIH NIH R01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2024 · $466,775

## Abstract

Project Summary
 Pre-sympathetic neurons (PSNs) of the hypothalamic paraventricular nucleus (PVN) are essential drivers of
physiological and pathological increases of sympathetic nerve activity (SNA). Perhaps their most robust property is
their resting state of discharge quiescence. Early studies linked quiescence to the dominance of synaptic inhibition,
but mechanisms that establish and defend GABAergic inhibitory tonus in the PVN are understood only on a
rudimentary level. This is an important knowledge gap because pathogenic factors that increase PVN-driven SNA
must ultimately subvert or overwhelm mechanisms that regulate the quiescent resting state of PSNs. In preliminary
studies, we uncovered a presynaptic mechanism that is novel to the PVN, referred to as “Glutamate-GABA
strengthening (GGS)”, that increases GABAergic inhibition in pace with synaptic glutamate (Glu) spillover. To do so,
GGS regulates the amplitude of GABA-A receptor-mediated inhibitory postsynaptic currents (IPSCs) through uptake
of synaptically released Glu, ostensibly into local GABA terminals, by the neuronal excitatory amino acid transporter
3 (EAAT3). Once internalized, Glu is converted to GABA and GABA molecules are packaged into synaptic vesicles
at greater than normal density. Stressors that acutely increase PVN-driven SNA are hypothesized to increase
synaptic Glu release without changing extrinsic GABAergic input. As a result, “over-filled” GABA vesicles are
released that dampen excitation and aid restoration of PSN quiescence. During chronic sympathoexcitation
challenges accompanied by reduced GABA input, GGS is subverted (due to low GABA release) and can therefore
provide little opposition to synaptic excitation. Proposed studies will use state-of-the-art transgenic mouse models,
optogenetics and virus-mediated gene over-expression and CRISPR-Cas9 knockdown to assess mechanisms and
functional outcomes of GGS. Kinetics, sensitivity and efficacy of GGS will be established at the single PSN level
using a novel horizontal brain slice preparation that preserves Glu input from the forebrain median preoptic nucleus
(MnPO) as well as GABA input from the PVN peri-nuclear zone (PNZ). Retrogradely transported AAV will be injected
into the PVN of vGlut2-Cre mice to express channelrhodopsin (ChR2) in glutamatergic MnPO-PVN neurons.
Optogenetic activation will determine the capacity of MnPO inputs to drive GGS amongst RVLM-projecting PVN
PSNs. Using vGlut2fl/fl mice, we will determine functional effects of GGS on GABA-A receptor inhibitory tone and
SNA responses to forebrain angiotensin II (AngII) and hyperosmolality when glutamatergic MnPO neurons have
normal (vGlut2 intact) or diminished (vGlut2 knockdown) capacity to release Glu from PVN synapses. To further
illuminate in vivo mechanisms and efficacy of GGS, EAAT3 on PNZ GABA inputs to the PVN will be increased and
decreased to grade PVN GABAergic tonus and the magnitude of PVN-driven SNA responses to (1) acute forebrain
Ang...

## Key facts

- **NIH application ID:** 11137377
- **Project number:** 7R01NS115072-05
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** GLENN M TONEY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $466,775
- **Award type:** 7
- **Project period:** 2024-06-01 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11137377

## Citation

> US National Institutes of Health, RePORTER application 11137377, Mechanisms of Synaptic Homeostasis Governing Pre-Sympathetic Neurons in the Hypothalamic Paraventricular Nucleus (7R01NS115072-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/11137377. Licensed CC0.

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