Summary: Using a stress-based mouse model, researchers have identified the gene LHPP as a key modulator that interacts with stress to drive features of treatment-resistant major depressive disorder (MDD). In stressed animals, elevated LHPP worsened depression-like behaviors, and those behaviors were relieved by esketamine but not by a standard antidepressant.
This study highlights how genetic vulnerability and environmental stress work together in MDD. By focusing on LHPP, which acts at neuronal synapses, the researchers mapped a molecular pathway linking LHPP activity to decreases in BDNF and PSD95 via reduced phosphorylation of CaMKIIα and ERK, changes associated with depressive-like outcomes in mice.
Key Facts:
- LHPP is identified as a stress-responsive gene: increased LHPP expression in stressed mice amplified depression-like behaviors.
- Certain human LHPP mutations (E56K, S57L) appear to boost CaMKIIα/ERK–BDNF/PSD95 signaling and may have protective or antidepressant-like effects.
- Behavioral deficits driven by LHPP upregulation responded to esketamine in mice, while the conventional antidepressant fluoxetine did not, suggesting relevance for treatment-resistant depression.
Source: Elsevier
Major depressive disorder (MDD) is a common, often disabling mental illness that arises from both genetic and environmental factors.
In a new study published in Biological Psychiatry, investigators report that LHPP interacts with stress to influence a form of depression-like behavior that resists conventional antidepressant treatment in an animal model.
Jing Zhang, PhD, of Fujian Medical University and senior author of the study, emphasized the importance of studying gene-by-environment interactions: “Emerging evidence suggests that MDD is a consequence of the co-work of genetic risks and environmental factors, so it is crucial to explore how stress exposure and risk genes co-contribute to the pathogenesis of MDD.”
The team used the chronic social defeat stress (CSDS) paradigm, a well-established mouse model in which animals are repeatedly exposed to an aggressor for two weeks, producing social avoidance and other depression-like behaviors. They focused on LHPP, a phosphatase that regulates phosphorylation at multiple residues and interacts with synaptic signaling networks in glutamatergic neurons.
In mice subjected to CSDS, LHPP was upregulated specifically in glutamatergic neurons of the ventral hippocampus. This increase impaired neuronal signaling: LHPP reduced phosphorylation of the protein kinases CaMKIIα and ERK, which in turn lowered expression of synaptic and neurotrophic markers BDNF and PSD95. These molecular changes correlated with reduced dendritic spine density and lower excitability of CA1 pyramidal neurons—features associated with depressive-like behaviors.
Genetic manipulations supported a causal role for LHPP. Conditional knockout of LHPP in glutamatergic neurons improved baseline activity and conferred resilience to CSDS. Similarly, targeted knockdown of LHPP in the ventral hippocampus via adeno-associated virus made mice more resistant to stress. Conversely, raising LHPP levels produced depression-like outcomes.
Importantly, the authors compared human LHPP variants with the wild-type gene and found that two human mutations, E56K and S57L, enhanced CaMKIIα/ERK–BDNF/PSD95 signaling relative to the native LHPP. Based on these molecular effects, the authors suggest that such variants might have an antidepressant influence in people carrying them.
The study also examined treatment responses. Whereas the selective serotonin reuptake inhibitor fluoxetine failed to reverse LHPP-driven behavioral deficits, a single treatment with esketamine markedly alleviated the depression-like behaviors induced by LHPP upregulation. This differential response indicates that LHPP-related mechanisms may underlie certain treatment-resistant forms of depression that respond preferentially to NMDA-receptor modulators like ketamine or esketamine.
John Krystal, MD, Editor of Biological Psychiatry, commented on the implications: “We have limited understanding of the neurobiology of treatment-resistant forms of depression. This study identifies a depression risk mechanism for stress-related behaviors that fail to respond to a standard antidepressant but respond well to ketamine. This may suggest that the risk mechanisms associated with the LHPP gene shed light on the poorly understood biology of treatment-resistant forms of depression.”
Dr. Zhang added, “Together, our findings identify LHPP as an essential player driving stress-induced depression, implying targeting LHPP as an effective strategy in MDD therapeutics in the future.”
About this major depressive disorder research news
Author: Eileen Leahy
Source: Elsevier
Contact: Eileen Leahy – Elsevier
Image: The image is credited to Neuroscience News
Original Research: Closed access.
“LHPP in glutamatergic neurons of the ventral hippocampus mediates depression-like behavior by dephosphorylating CaMKIIα and ERK” by Jing Zhang et al., Biological Psychiatry
Abstract
LHPP in glutamatergic neurons of the ventral hippocampus mediates depression-like behavior by dephosphorylating CaMKIIα and ERK
Background
Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) has been implicated as a genetic risk factor for major depressive disorder. LHPP acts as a phosphatase for multiple amino-acid residues, including histidine, serine, threonine, and tyrosine, but its specific contributions to depression-related biology were not well defined.
Methods
The study combined genetic tools, molecular assays, behavioral testing, and electrophysiology to determine how LHPP influences neuronal function and stress-related behavior in mice.
Results
LHPP levels were elevated in glutamatergic neurons of the ventral hippocampus in mice showing stress-induced depressive behaviors. Removing LHPP from glutamatergic neurons (LHPPflox/flox·CaMKIIαCre+ conditional knockout) improved baseline activity and resilience to stress. Viral knockdown of LHPP in the ventral hippocampus also promoted resistance to chronic social defeat stress.
Altering LHPP expression changed dendritic spine density and CA1 pyramidal neuron excitability by modulating BDNF and PSD95 expression through dephosphorylation of CaMKIIα and ERK. Human LHPP mutants (E56K, S57L) increased activity of the CaMKIIα/ERK–BDNF/PSD95 signaling pathway compared with wild-type LHPP. Finally, esketamine—but not fluoxetine—substantially reversed the behavioral effects of LHPP upregulation.
Conclusions
These findings indicate that LHPP contributes to depression-related neural changes through its phosphatase activity on threonine and serine residues and identify LHPP as a promising target for future therapeutic strategies in MDD, particularly for forms of depression that are resistant to conventional antidepressants.