Loss of synaptic zinc transport in progranulin deficient mice may contribute to progranulin-associated psychopathology and chronic pain

Sensory processing of nociception involves primary nociceptive neurons in the DRGs, secondary projection neurons in the dorsal horn of the spinal cord, the dorsolateral thalamus and somatosensory cortex (SSC, S1). This direct path is connected to the prefrontal cortex (PFC), the insula cortex and the limbic system including amygdala, anterior cingulate cortex (ACC), nucleus accumbens (NAc), areas of the midbrain (e.g. VTA, ventral tegmental area; PAG, periaquaeductal grey) and hippocampus. These areas process the cognitive and affective modulation of 'pain'. As a result, chronic pain in humans is associated with changes of mood, interest and cognition. The present study assessed these sequelae in a model of neuropathic pain in mice with a deficiency of progranulin (Grn−/−). At old age, these mice develop signs of frontotemporal dementia (FTD) and are a model for this neurodegenerative disease. Nerve injury precipitated pathological behavior in Grn−/− mice reminiscent of the human FTD disease including hyperactivity, lack of attention, compulsive feeding, loss of shelter seeking, and depression-like behavior, which were not evident at this age without the injury. Heat maps of nociception exemplarily show the time course of neuropathic pain. Psychopathologic sequelae did not occur without pain persistence in mice overexpressing progranulin in DRG neurons (SNS-Grn-OE). A deep proteome analysis of the PFC and olfactory bulb identified differentially expressed proteins involved in transport mechanisms at the synapse (examples of synaptic proteins are presented), in particular synaptic vesicle zinc transporters suggesting that progranulin deficiency alters synaptic zinc homeostasis and thereby increases the vulnerability for pathological sensory and affective processing of neuropathic 'pain'. Loss of the synaptic zinc transporter, Znt3, has been associated with dementia, neuropsychiatric disease like autism and schizophrenia and intensified neuropathic pain. Synaptic zinc reduces glutamate evoked excitability of NMDA and AMPA receptors and strengthens glycinergic inhibitory currents. Hence, the observed ZnT3 deficiency explains at least in part the combination of increased pain, psychopathology and early manifestation of dementia in nerve injured Grn−/− mice.233