Glutamate theories of schizophrenia suggest that the disease is associated with a loss of NMDA receptors, specifically on GABAergic parvalbumin-expressing interneurons (PVIs), leading to changes in the excitation–inhibition balance in the prefrontal cortex (PFC). Oxidative stress contributes to the loss of PVI and the development of schizophrenia. Here, we investigated whether the glutathione precursor N-acetyl cysteine (NAC) can prevent changes in synaptic transmission at pyramidal cells and PVIs that result from developmental NMDAR blockade and how these changes are related to mitochondrial dysfunction in the PFCs of mice. Perinatal treatment with ketamine induced persistent changes in the reduced glutathione/oxidized glutathione (glutathione disulfide) ratio in the medial PFC, indicating long-lasting increases in oxidative stress. Perinatal ketamine treatment also reduced parvalbumin expression, and it induced a decline in mitochondrial membrane potential, as well as elevations in mitochondrial superoxide levels. At the level of synaptic function ketamine reduced inhibition onto layer 2/3 pyramidal cells and increased excitatory drive onto PVI, indicating long-lasting disruptions in the excitation–inhibition balance. These changes were accompanied by layer-specific alterations in NMDAR function in PVIs. All of these changes were mitigated by coadministration of NAC. In addition, NAC given only during late adolescence was also able to restore normal mitochondria function and inhibition at pyramidal cells. These results show that ketamine-induced alterations in PFC physiology correlate with cell type-specific changes in mitochondria function. The ability of NAC to prevent or restore these changes supports the usefulness of antioxidant supplementation in the treatment of schizophrenia.

Understanding masseter muscle (MM) innervation is critical for the study of cell-specific mechanisms of pain induced by temporomandibular disorder (TMDs) or after facial surgery. Here, we identified trigeminal (TG) sensory neuronal subtypes (MM TG neurons) innervating MM fibers, masseteric fascia, tendons, and adjusted tissues. A combination of patch clamp electrophysiology and immunohistochemistry (IHC) on TG neurons back-traced from reporter mouse MM found nine distinct subtypes of MM TG neurons. Of these neurons, 24% belonged to non-peptidergic IB-4 + /TRPA1 – or IB-4 + /TRPA1 + groups, while two TRPV1 + small-sized neuronal groups were classified as peptidergic/CGRP + . One small-sized CGRP + neuronal group had a unique electrophysiological profile and were recorded from Nav1.8 – or trkC + neurons. The remaining CGRP + neurons were medium-sized, could be divided into Nav1.8 – /trkC – and Nav1.8 low /trkC + clusters, and showed large 5HT-induced current. The final two MM TG neuronal groups were trkC + and had no Nav1.8 and CGRP. Among MM TG neurons, TRPV1 + /CGRP – (somatostatin + ), tyrosine hydroxylase (TH) + (C-LTMR), TRPM8 + , MrgprA3 + , or trkB + (Aδ-LTMR) subtypes have not been detected. Masseteric muscle fibers, tendons and masseteric fascia in mice and the common marmoset, a new world monkey, were exclusively innervated by either CGRP + /NFH + or CGRP – /NFH + medium-to-large neurons, which we found using a Nav1.8-YFP reporter, and labeling with CGRP, TRPV1, neurofilament heavy chain (NFH) and pgp9.5 antibodies. These nerves were mainly distributed in tendon and at junctions of deep-middle-superficial parts of MM. Overall, the data presented here demonstrates that MM is innervated by a distinct subset of TG neurons, which have unique characteristics and innervation patterns.

Myogenous temporomandibular disorders (TMD-M) are the most prevalent group of painful orofacial conditions, and the second most frequent among musculoskeletal pain conditions. TMD-M is associated with an increased responsiveness of nerves innervating the masseter (MM), temporal (TM), medial pterygoid closing (MPM) and lateral pterygoid gliding muscles (LPM). Treatment of this disorder remains difficult and is further complicated by each muscle having diverse and functionally distinct nerve innervation. This study examined expression of sensory markers in MM, TM and LPM of adult male common marmosets, a type of non-human primate. Using immunohistochemistry, we found that masticatory muscles were predominantly innervated with A-fibers (NFH+). All C-fibers (pgp9.5+/NFH-) observed in masticatory muscles were peptidergic (CGRP+) and lacked antibody labeling for mrgprD, trpV1 and the silent nociceptive marker, CHRNA3. The proportion of C- to A-fibers was highest in LPM, while MM had a minimal percentage (6-8%) of C-fibers. Interestingly, C-fibers in masticatory muscle may have myelin sheath, since many NFH- nerves were labeled with GFAP+. A-fiber types were also dissimilar among these muscles. Thus, there are substantially more peptidergic A-fibers (CGRP+/NFH+) in TM and LPM compared to MM. Almost all A-fibers in MM expressed trkC, with some of them having trkB and parvalbumin (PV). In contrast, a lesser number of TM and LPM nerves expressed trkC, lacked trkB and had fewer PV+ fibers in LPM. Along with sensory fibers, the masticatory muscles contain sympathetic fibers (tyrosine hydroxylase; TH+), which are located around blood vessels. This TH expression was absent in trigeminal neurons. Overall, the masticatory muscles of male marmosets have distinct expression patterns when compared to each muscle of the jaw and cutaneous fibers innervated by DRG neurons.

Karen Lindquist, director at MCE, discusses the opportunities for HR to act as a strategic partner during mergers and acquisitions.

Redox dysregulation and oxidative stress are final common pathways in the pathophysiology of a variety of psychiatric disorders, including schizophrenia. Oxidative stress causes dysfunction of GABAergic parvalbumin-positive interneurons (PVI), which are crucial for the coordination of neuronal synchrony during sensory- and cognitive-processing. Mitochondria are the main source of reactive oxygen species (ROS) in neurons and they control synaptic activity through their roles in energy production and intracellular calcium homeostasis. We have previously shown that in male mice transient blockade of NMDA receptors during development (subcutaneous injections of 30 mg/kg ketamine (KET) on postnatal days 7, 9, and 11) results in long-lasting alterations in synaptic transmission and reduced parvalbumin expression in the adult prefrontal cortex (PFC), contributing to a behavioral phenotype that mimics multiple symptoms associated with schizophrenia. These changes correlate with oxidative stress and impaired mitochondrial function in both PVI and pyramidal cells. Here, we show that genetic deletion (Ppif-/-) of the mitochondrial matrix protein cyclophilin D (CypD) prevents perinatal KET-induced increases in ROS and the resulting deficits in PVI function, and changes in excitatory and inhibitory synaptic transmission in the PFC. Deletion of CypD also prevented KET-induced behavioral deficits in cognitive flexibility, social interaction, and novel object recognition. Taken together, these data highlight how mitochondrial activity may play an integral role in modulating PVI-mediated cognitive processes.Significance StatementMitochondria are important modulators of oxidative stress and cell function, yet how mitochondrial dysfunction affects cell activity and synaptic transmission in psychiatric illnesses is not well understood. NMDA receptor blockade with ketamine during development causes oxidative stress, dysfunction of parvalbumin-positive interneurons (PVI), and long-lasting physiological and behavioral changes. Here we show that mice deficient for the mitochondrial matrix protein cyclophilin D show robust protection from PVI dysfunction following perinatal NMDAR-blockade. Mitochondria serve as an essential node for a number of stress-induced signaling pathways and our experiments suggest that failure of mitochondrial redox regulation can contribute to PVI dysfunction.