Dysregulation of adult hippocampal neuroplasticity in major depression: pathogenesis and therapeutic implications

Abstract

Major depressive disorder (MDD) was previously hypothesized to be a disease of monoamine deficiency in which low levels of monoamines in the synaptic cleft were believed to underlie depressive symptoms. More recently, however, there has been a paradigm shift toward a neuroplasticity hypothesis of depression in which downstream effects of antidepressants, such as increased neurogenesis, contribute to improvements in cognition and mood. This review takes a top-down approach to assess how changes in behavior and hippocampal-dependent circuits may be attributed to abnormalities at the molecular, structural, and synaptic level. We conclude with a discussion of how antidepressant treatments share a common effect in modulating neuroplasticity and consider outstanding questions and future perspectives.

Figure 1:. Hippocampus Anatomy.

The hippocampus is divided into multiple subregions including the dentate gyrus (DG), Cornu Ammonis (CA) regions 1-4, and subiculum (not shown). The entorhinal cortex (EC) acts as the gateway into the hippocampus via the perforant path which projects onto the DG (1). The DG sends fibers to CA3 through the mossy fiber pathway (2). CA3 pyramidal cells receive inputs from the associated/commissural fibers (not shown) and send their projections to CA1 via Schaffer collaterals (3). Lastly, neurons in CA1 project back into the entorhinal cortex and into subiculum (4).

Figure 2:. Mechanisms of Synaptic Plasticity.

Left: Under basal conditions, glutamate is released from the pre-synaptic neuron. Once in the synaptic cleft, glutamate stimulates AMPA receptors on the post-synaptic neuron, triggering depolarization noted by the influx of sodium ions. With a weak stimulus, influx of sodium into the pre-synaptic neuron is minimal and infrequent, resulting in infrequent and low amplitude excitatory postsynaptic potentials (EPSPs). Right: Under high levels of stimulation, more glutamate is released from the pre-synaptic neuron resulting in stronger depolarizations on the post-synaptic neuron. Stronger depolarization increases the amount of calcium in the cell and removes magnesium from NMDA receptors, allowing more sodium to enter. High intracellular calcium levels activate kinases like Protein Kinase C (PKC) and Calcium/Calmodulin dependent protein kinase II (CaKMII) which phosphorylates AMPA receptors thereby increasing their conductance. In both scenarios, glial cells present at the synaptic cleft aid in glutamate reuptake.

Figure 3.. Molecular Regulators of Neuroplasticity.

Brain-derived neurotrophic factor (BDNF) attaches to a Tropomyosin receptor kinase B (TrkB) receptor on the post-synaptic neuron. BDNF signaling causes expression of phosphoinositide 3-kinase (PI3K) which is responsible for cell proliferation and survival. PI3K activates Protein Kinase B (Akt) and Mitogen-activated protein kinase (MEK) pathways which lead to expression of cAMP response element binding protein (CREB) and mammalian target or rapamycin (mTOR), respectively. High intracellular Ca²⁺ concentrations from AMPA and NMDA activation activate CAMKII which also stimulates CREB production. CREB is a key element needed for neurite outgrowth, neurogenesis and synaptic plasticity.

Figure 4.. Before and After Treatment.

Table shows cognitive/behavioral, network/circuit, neuron structure and number, synapse function and signaling pathways alterations in untreated and treated depression.