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They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses. Credit: Neuroscience News

New Gene Link to Treatment-Resistant Depression

Summary: Researchers discovered a gene, LHPP, that interacts with stress and plays a pivotal role in treatment-resistant Major Depressive Disorder (MDD) using an animal model.

This groundbreaking study underscores the intricate dance between genetic risks and environmental factors in the onset of MDD. In stressed mice, an increase in LHPP expression worsened depression-like behaviors.

Notably, this form of depression responded positively to esketamine, but not traditional antidepressants.

Key Facts:

  1. LHPP is a newly identified gene that, when expressed more, aggravates depression-like behaviors in stress-induced mice models.
  2. Mutations in the LHPP gene may carry potential antidepressant effects in humans.
  3. While traditional drugs like fluoxetine showed no effect, esketamine alleviated the LHPP-induced depression-like behaviors in mice.

Source: Elsevier

Major depressive disorder (MDD) is a widespread mental health condition that for many is disabling. It has long been appreciated that MDD has genetic as well as environmental influences.

In a new study in Biological Psychiatry, researchers identify a gene that interacted with stress to mediate aspects of treatment-resistant MDD in an animal model.

Jing Zhang, PhD, at Fujian Medical University and senior author of the study, said, “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.”

To do that, the authors used a mouse model of stress-induced depression called chronic social defeat stress (CSDS) in which mice are exposed to aggressor mice daily for two weeks. They focused on a gene called LHPP, which interacts with other signaling molecules at neuronal synapses.

Increased expression of LHPP in the stressed mice aggravated the depression-like behaviors by decreasing expression of BDNF and PSD95 by dephosphorylating two protein kinases, CaMKIIα and ERK, under stress exposure.

Dr. Zhang noted, “Interestingly, LHPP mutations (E56K, S57L) in humans can enhance CaMKIIα/ERK-BDNF/PSD95 signaling, which suggests that carrying LHPP mutations may have an antidepressant effect in the population.”

MDD is an extremely heterogeneous condition. Differences in the types of depression experienced by people influence the way they respond to treatment. A large subgroup of people with depression fail to respond to standard antidepressant medications and have “treatment-resistant” symptoms of depression.

These patients often respond to different medications, such as ketamine or esketamine, or to electroconvulsive therapy. Notably, esketamine markedly alleviated LHPP-induced depression-like behaviors, whereas the traditional drug fluoxetine did not, suggesting that the mechanism might underlie some types of treatment-resistant depression.

John Krystal, MD, Editor of Biological Psychiatry, said of the work, “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


LHPP in glutamatergic neurons of the ventral hippocampus mediates depression-like behavior by dephosphorylating CaMKIIα and ERK


Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) was recently shown to be a risk gene for major depressive disorder (MDD). LHPP has been proven to dephosphorylate the residues of histidine, serine, threonine, and tyrosine. However, much remains unknown regarding how LHPP contributes to depression.


The present study addressed this issue by integrating approaches of genetics, molecular biology, behavioral testing and electrophysiology.


We have discovered here that the levels of LHPP was upregulated in the glutamatergic neurons of the ventral hippocampus (vHip) in mice that displayed stress-induced depression-like behaviors. The knockout of LHPP in glutamatergic neurons of the brain improved the spontaneous activity of LHPPflox/flox·CaMKIIαCre+ (cKO) mice. Adeno-associated virus-mediated LHPP knockdown in the vHip enhanced resistance against chronic social defeat stress (CSDS) in mice.

Manipulations of LHPP levels impacted the density of dendritic spines and excitability of CA1 pyramidal neurons by mediating the expressions of BDNF and PSD95 via the modulation of the dephosphorylation of Calcium-calmodulin (CaM)-dependent protein kinase II α (CaMKIIα) and extracellular signal-regulated kinase (ERK).

Notably, compared with wild-type LHPP, human mutant LHPP (E56K, S57L) significantly increased the activity of the CaMKIIα/ERK-BDNF/PSD95 signaling pathway. Finally, esketamine, not fluoxetine, markedly alleviated the LHPP-upregulation-induced depression-like behaviors.


These findings show evidence that LHPP contributes to the pathogenesis of depression via threonine and serine hydrolases, signifying LHPP as a potential therapeutic target in treating MDD patients.

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