Deep brain stimulation: potential for neuroprotection

Abstract

Over the last two decades there has been an exponential rise in the number of patients receiving deep brain stimulation (DBS) to manage debilitating neurological symptoms in conditions such as Parkinson's disease, essential tremor, and dystonia. Novel applications of DBS continue to emerge including treatment of various psychiatric conditions (e.g. obsessive-compulsive disorder, major depression) and cognitive disorders such as Alzheimer's disease. Despite widening therapeutic applications, our understanding of the mechanisms underlying DBS remains limited. In addition to modulation of local and network-wide neuronal activity, growing evidence suggests that DBS may also have important neuroprotective effects in the brain by limiting synaptic dysfunction and neuronal loss in neurodegenerative disorders. In this review, we consider evidence from preclinical and clinical studies of DBS in Parkinson's disease, Alzheimer's disease, and epilepsy that suggest chronic stimulation has the potential to mitigate neuronal loss and disease progression.

Figure 1

Model of neuroprotective effects of DBS at the synapse. DBS stimulates increased BDNF release which induces structural and functional changes at the synapse by binding pre‐ and postsynaptic TrkB receptors. At the presynaptic terminal, activation of the cAMP‐PKA and MAPK pathways promotes increased presynaptic gene expression including key proteins involved in axonal growth and guidance (e.g. GAP 43) (1) and neurotransmitter vesicle release (e.g. synaptophysin, Rab3a) (2).90, 91, 92, 93, 94 MAPK phosphorylation of synapsin also releases neurotransmitter vesicles from cytoskeleton‐bound pools (3).95 TrkB‐mediated activation of PLC γ increases intracellular Ca²⁺ concentration leading to increased presynaptic neurotransmitter release (4).90 At the postsynaptic terminal, TrkB activation leads to tyrosine phosphorylation of NMDA‐type glutamate receptor (NMDAR) subunits, increasing conductance (5).96, 97 Activation of the PLC γ pathway induces a rise in intracellular Ca²⁺ concentration and subsequent activation of Ca²⁺/calmodulin‐dependent kinase II (CaMKII) and protein kinase C (PKC), which phosphorylate AMPA‐type glutamate receptors (AMPAR) subunits and increase their delivery to the postsynaptic terminal (6).98 Elevated Ca²⁺ levels may also activate transcription factor EB (TFEB), which is the major regulator of autophagy and could enhance clearance of toxic misfolded proteins (7).70, 99 TrkB‐mediated activation of cAMP response element binding protein (CREB) and Erk enhances gene transcription (8).25 BDNF‐TrkB signaling also enhances postsynaptic protein translation through both MAPK/Erk and PI3K/Akt pathways (9).25 The PI3K/Akt pathway is also involved in regulating the trafficking of proteins (e.g. PSD95) to the postsynaptic terminal (10)25 and inhibition of apoptosis (11).100, 101