Eliminating the VGlut2-Dependent Glutamatergic Transmission of Parvalbumin-Expressing Neurons Leads to Deficits in Locomotion and Vocalization, Decreased Pain Sensitivity, and Increased Dominance

Abstract

The calcium-binding protein parvalbumin (PV) is a recognized marker of short-axon GABA-ergic neurons in the cortex and the hippocampus. However in addition, PV is expressed by excitatory, glutamatergic neurons in various areas of the brain and spinal cord. Depending on the location of these neurons, loading of their synaptic vesicles with glutamate is mediated by either of three vesicular glutamate transporters (VGlut): VGlut1, VGlut2, or VGlut3. Driven by our interest in one of these glutamatergic/PV-expressing cell clusters—the lateral hypothalamic parvafox nucleus—we investigated the functions of this population of neurons by the selective deletion of VGlut2 expression in PV-expressing cells according to the Cre/Lox-approach. PV-Cre;VGlut2-Lox mutant mice are phenotypically characterized by deficits in locomotion and vocalization, by a decreased thermal nociception, and by an increased social dominance. We conducted a search of the Allen Brain Atlas for regions that might co-express the genes encoding PV and VGlut2, and that might thus contribute to the manifestation of the observed phenotypes. Our survey revealed several structures that could contribute to the deficits in locomotion and vocalization, such as the red, the subthalamic and the deep cerebellar nuclei. It also disclosed that a shift in the balance of afferental glutamatergic neurotransmission to the periaqueductal gray matter might be accountable for the decrease in sensitivity to pain and for the increase in social dominance. As a whole, this study broadens the state of knowledge about PV-expressing excitatory neurons.

Lateral hypothalamic fast-spiking parvalbumin neurons modulate nociception through connections in the periaqueductal gray area

“…Moreover, our findings and those of others showing that LH PV neurons send long-range projections to several brain regions involved in reward, motivation, and nociception 15,16 suggest that these neurons may be essential for regulating survival behaviors. In further support, chemical ablation of LH PV neurons in rats 17 or conditional inactivation of glutamatergic signaling of parvalbumin-expressing neurons in mice 18 decreased vocalization and locomotion, respectively. In addition, decreased thermal nociception and increased social dominance were also observed in these knockout mice 18 .…”

“…In further support, chemical ablation of LH PV neurons in rats 17 or conditional inactivation of glutamatergic signaling of parvalbumin-expressing neurons in mice 18 decreased vocalization and locomotion, respectively. In addition, decreased thermal nociception and increased social dominance were also observed in these knockout mice 18 . However, a potential confounding factor in these studies might be the selective deletion of vesicular glutamate transporter 2 ( Slc17a6, i.e.…”

“…Here, we find that increased LH PV neuronal activity suppresses nociception to a noxious thermal stimulus in mice, whereas inhibition of neuronal activity causes hypersensitivity. Interestingly, previous studies showed that mice with conditional deletion of glutamatergic signaling in PV-expressing neurons display a phenotype characterized by decreased thermal nociception, deficits in locomotion, and increased social dominance 18 . However, as stated in the study, the observed findings are suggestive as genetic compensation in response to a gene knockout is a widespread phenomenon 34 .…”

VGLUT2/Cdk5/p25 Signaling Pathway Contributed to Inflammatory Pain by Complete Freund’s Adjuvant

“…Previous studies have established that VGLUT including subtype 1, 2, and 3 are expressed in distinct populations of glutamatergic neurons and play multiple roles in the central nervous system [3]. However, VGLUT2, but not VGLUT1 and 3, plays a key role in mediating pain hypersensitivity induced by inflammation and peripheral nerve injury [4][5][6][7][8].…”

“…e coexpression of VGLUT2 and two main nociceptors of calcitonin gene-related peptide (CGRP) and transient receptor potential channel (TRPV1) was observed in small-and medium-sized neurons of the dorsal root ganglion (DRG) in mice [4][5][6][7][8]. Additionally, VGLUT2 knock-out mice challenged with CFA demonstrates a complete loss of heat hyperalgesia, whereas mechanical hypersensitivity induced by CFA remains intact.…”