ELUCIDATION OF MECHANISMS THAT DETERMINE THE RESPONSIVENESS TO ANTIDEPRESSANT DRUG TREATMENTS
Open Access
- Author:
- Feng, Mengyang
- Graduate Program:
- Molecular, Cellular and Integrative Biosciences
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- June 25, 2019
- Committee Members:
- Bernhard Luscher, Dissertation Advisor/Co-Advisor
Bernhard Luscher, Committee Chair/Co-Chair
Melissa Rolls, Committee Member
Timothy J Jegla, Committee Member
Pamela Hankey Giblin, Outside Member
Jeffrey Maurice Peters, Committee Member - Keywords:
- Depression
Antidepressant
Neuroinflammation
High fat diet
Obesity
Ketamine - Abstract:
- Major depressive disorder (MDD) is a prevalent and debilitating psychiatric syndrome affecting approximately 4.4% of the worldwide. The therapeutic onset of currently available antidepressants is delayed by several weeks. About one third of MDD patients suffer from treatment resistant depression (TRD), meaning they do not respond to two or more different classes of conventional antidepressants. Although the rapid acting antidepressant ketamine exerts rapid and lasting antidepressant effects in more than half of TRD patients, ketamine still fails in some TRD patients, especially those associated with chronic inflammatory conditions. Increasing clinical evidence suggests that neuroinflammation is associated with increased vulnerability to MDD and poor response to antidepressants, however the neurophysiological changes that underlie treatment resistance remain to be elucidated. Recent preclinical studies suggest chronic exposure to high fat diet (HFD) in rodents induces a depressive-like brain state associated with heightened neuroinflammation and disrupted glucose homeostasis. Here we first confirmed that chronic HFD exposure of C57BL/6J mice results in abnormal glucose metabolism and neuroinflammation, as well as an anxious-depressive-like behavioral phenotype. We then assessed whether this HFD-induced depressive-like brain state is suitable to model treatment resistance. Indeed, we found that chronic HFD-induced anxious-depressive-like behavioral deficits are largely resistant to treatment with conventional antidepressants such as desipramine and fluoxetine, as well as to treatment with ketamine. Whole-cell patch clamp recordings of pyramidal cells in the prelimbic cortex (PLC) of HFD exposed mice revealed increased intrinsic excitability and increased hyperpolarization-activated cation currents (Ih currents). Based on these findings, we selected the voltage-gated K+ (Kv7 or KCNQ) channel opener retigabine and tested antidepressant effects of retigabine in a battery of behavioral tests. Subchronic retigabine treatment significantly ameliorated chronic HFD-induced anxious-depressive-like behaviors, and iii iv these effects were associated with normalized neural excitability and Ih currents. Our data suggest that increased intrinsic neural excitability may underlie the chronic HFD-induced treatment- resistant depressive-like brain state that can be normalized pharmacologically by agents that reduce neural excitability. Previous preclinical studies from our lab showed that heterozygous deletion of the γ2 subunit (Gabrg2) of the γ-aminobutyric acid type A receptors (GABAARs) in mice (γ2+/- mice) results in modest defects in GABAergic neurotransmission and an anxious-depressive-like phenotype, whereas increasing synaptic inhibition of principle cells by genetically increasing the excitability of somatostatin (SST)-positive GABAergic interneurons (i.e. in SSTCre:γ2f/f mice) results in an antidepressant-like phenotype that mimics the effects of antidepressant drug treatment. Therefore, we hypothesized that a shift in the synaptic excitation to inhibition ratio (E:I ratio) towards increased excitation promotes anxiety and depression-related phenotypes while reducing this ratio result in an anxiolytic-antidepressant-like phenotype. Here we tested whether positive and negative shifts in E:I ratio of γ2+/- and SSTCre: γ2f/f would ameliorate or exacerbate the chronic HFD-induced depressive-like states. We found no significant differences in HFD- induced anxious-depressive-like behavioral deficits in γ2+/- and SSTCre: γ2f/f mice compared to WT mice with a battery of behavioral tests, suggesting that chronic HFD and synaptic E:I ratio changes mediate anxious-depressive-like states via distinct mechanisms. A recent study from our lab further demonstrated that functional defects in GABAergic synapses in γ2+/- mice lead to homeostatic-like downregulation in surface level of N-Methyl-D- aspartic acid type glutamate receptors (NMDARs) and α-amino-3-hydroxy-5-methyl-4- isoxazolepropionic acid type glutamate receptors (AMPARs) that can be normalized with a single subanesthetic dose of ketamine. Given that the anxious-depressive-like behavioral deficits in γ2+/- mice can be ameliorated with single subanesthetic dose of ketamine and chronic desipramine, we v speculated that the homeostatic upregulation of glutamatergic and GABAergic synapses also contributes to the antidepressant effects of conventional antidepressants. Preliminary results showed that chronic treatment of γ2+/- mice with desipramine and fluoxetine leads to downregulation rather than upregulation of NMDARs, in contrast to ketamine. This indicates that conventional antidepressants and ketamine may exert antidepressants via different mechanisms. In summary, my dissertation established a chronic HFD-induced mouse model that is useful to study neuroinflammation-associated treatment-resistant depressive-like brain states. This brain state revealed increased intrinsic neural excitability and Ih currents as promising targets for development of future antidepressants. Moreover, the results showed that chronic HFD and changes in synaptic E:I ratio affect emotional states through distinct neural mechanisms. Lastly, preliminary results suggested that different antidepressant agents may exert antidepressant effects through different mechanism of neural plasticity.