Alterations in AMPA and GABA signal transmission in the hippocampus in major depression

602 

Abstract Submission 

Jessica Gilbert¹, Carlos Zarate¹

¹NIMH/NIH, Bethesda, MD

Jessica Gilbert  
NIMH/NIH
Bethesda, MD

Carlos Zarate  
NIMH/NIH
Bethesda, MD

Patients with major depression (MD) exhibit deficits in working memory (WM) and disrupted neuroplasticity within the hippocampus. Hippocampal memory processes, hypothesized to be supported by gamma oscillatory activity, can be measured using tasks such as the n-back. Gamma rhythms are considered to be a proxy measure of excitation-inhibition balance (Buzsáki and Wang 2012), and changes in gamma in the psychiatric state are thought to reflect dysregulation of homeostatic balance. An emerging pathophysiological feature of MDD includes changes in gamma band rhythms (Fitzgerald and Watson 2018). This study used an n-back task in tandem with magnetoencephalography (MEG) to assess WM network-level differences between MDs and healthy participants (HCs).

MEG data were recorded using a CTF 275-channel system while participants (MDD=39, HC=21) completed an n-back task. Accuracy and reaction time (RT) were calculated for the 0-, 1-, and 2-back conditions, and Mann-Whitney tests were used to examine behavioral differences. MEG source-level gamma (30-58 Hz) power was projected using the multiple sparse priors algorithm in SPM12 using two peristimulus time windows of interest: -500-0 ms and 0-500 ms, corresponding to the maintenance and retrieval periods of the task. Linear mixed effects models tested for group (MD and HC), condition (0-, 1-, and 2-back), and group-by-condition interactions. Dynamic causal modeling (DCM) was used to model effective connectivity between regions of interest identified from the group-level results, including the cingulate, orbitofrontal cortex, and hippocampus, using a biophysical that included parameters governing AMPA, NMDA, and GABA signaling. Parametric empirical Bayesian analysis was used to identify parameters that differed between groups, using a posterior probably of ≥0.95.

There were significant differences for 2-back accuracy and RT between groups, with MDs having lower accuracy (MD mean=74.03+21.42, HC mean=89.24+9.70, p=0.01) and increased RT (MD mean=0.49+0.23, HC mean=0.3+0.16, p=0.03) relative to HCs. In gamma, increasing WM load was associated with increasing power in bilateral intraparietal sulcus for the 0-to-1-back and 0-to-2-back conditions during the maintenance period across groups (p_FDR<0.05). In addition, MDs had increased gamma power in brain regions including the cingulate, orbitofrontal cortex, and hippocampus during maintenance compared to HCs (p_FDR<0.05). No significant gamma effects were found during the retrieval period. For the connectivity analysis, significantly increased AMPA time constants in all regions of interest and increased GABA time constants in hippocampus were found for MDs compared to HCs. The inverse of time constants are rate constants, suggesting slower AMPA and GABA signal transmission in these regions in MDs. In addition, the membrane capacitance of superficial and deep pyramidal cells was elevated for MDs compared to HCs, suggesting slower voltage change for these modeled cell types. Finally, the AMPA-mediated connectivity between orbitofrontal cortex and cingulate was reduced for MDs compared to HCs.

These results are consistent with studies reporting WM deficits at higher cognitive loads in individuals with MD. Dysregulated gamma oscillations, potentially mediated by AMPA and GABA signaling deficits in key brain network nodes supporting mood and WM performance, could account for these performance differences. Hippocampal neuroplasticity deficits in particular might be explained by slower AMPA and GABA signal transmission and altered homeostatic balance within this region. Future work will examine the relationship between depression severity and connectivity metrics in MDs.

Psychiatric (eg. Depression, Anxiety, Schizophrenia) ¹

Working Memory

EEG/MEG Modeling and Analysis ²

MEG

Memory

Modeling

Psychiatric Disorders