GRM7 deficiency, from excitotoxicity and neuroinflammation to neurodegeneration: Systematic review of GRM7 deficient patients.

The metabotropic glutamate receptor 7 (mGluR7) is a presynaptic G-protein-coupled glutamate receptor that modulates neurotransmitter release and synaptic plasticity at presynaptic terminals. It is encoded by GRM7, and recently variants have been identified in patients with autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay (DD), intellectual disability (ID), and brain malformations. To gain updated insights into the function of GRM7 and the phenotypic spectrum of genetic variations within this gene, we conducted a systematic review of relevant literature utilizing PubMed, Web of Science, and Scopus databases. Among the 14 articles meeting the inclusion criteria, a total of 42 patients (from 28 families) harboring confirmed mutations in the GRM7 gene have been documented. Specifically, there were 17 patients with heterozygous mutations, 20 patients with homozygous mutations, and 5 patients with compound heterozygous mutations. Common clinical features included intellectual behavioral disability, seizure/epilepsy, microcephaly, developmental delay, peripheral hypertonia and hypomyelination. Genotype-phenotype correlation was not clear and each variant had unique characteristics including gene dosage, mutant protein surface expression, and degradation pathway that result with a spectrum of phenotype manifestations through ASD or ADHD to severe DD/ID with brain malformations. Neuroinflammation may play a role in the development and/or progression of GRM7-related neurodegeneration along with excitotoxicity. The clinical and functional data presented here demonstrate that both autosomal dominant and recessive inheritance of GRM7 mutation can cause disease spectrum phenotypes through ASD or ADHD to severe DD/ID and seizure with brain malformations.

Adiponectin rescues synaptic plasticity in the dentate gyrus of a mouse model of Fragile X Syndrome.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is the leading known single-gene cause of autism spectrum disorder. Patients with FXS display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently, there is no cure for this condition; however, there is an emerging focus on therapies that inhibit mechanistic target of rapamycin (mTOR)-dependent protein synthesis owing to the clinical effectiveness of metformin for alleviating some behavioural symptoms in FXS. Adiponectin (APN) is a neurohormone that is released by adipocytes and provides an alternative means to inhibit mTOR activation in the brain. In these studies, we show that Fmr1 knockout mice, like patients with FXS, show reduced levels of circulating APN and that both long-term potentiation (LTP) and long-term depression (LTD) in the dentate gyrus (DG) are impaired. Brief (20 min) incubation of hippocampal slices in APN (50 nM) was able to rescue both LTP and LTD in the DG and increased both the surface expression and phosphorylation of GluA1 receptors. These results provide evidence for reduced APN levels in FXS playing a role in decreasing bidirectional synaptic plasticity and show that therapies which enhance APN levels may have therapeutic potential for this and related conditions.This article is part of a discussion meeting issue 'Long-term potentiation: 50 years on'.

A comparison of white matter microstructure and correlates with neuropsychological measures in younger and older adults.

OBJECTIVE: With a globally aging population, there is a need to better understand how brain structure relates to function in healthy older and younger adults. METHODS: 34 healthy participants divided into older (17; Mean = 70.9, SD = 5.4) and younger adults (17; Mean = 28.1, SD = 2.8) underwent diffusion-weighted imaging and neuropsychological assessment, including the California Verbal Learning Test 2nd Edition and the Trail Making Test (TMT-A and TMT-B). Differences in white matter microstructure for older and younger adults and the association between DTI metrics (fractional anisotropy, FA; mean diffusivity, MD) and cognitive performance were analyzed using tract-based spatial statistics (p < 0.05, corrected). RESULTS: Older adults had significantly lower FA and higher MD than younger adults in widespread brain regions. There was a significant negative correlation between executive function (TMT-B) and MD for older adults in the right superior/anterior corona radiata and the corpus callosum. No significant relationship was detected between DTI metrics and executive function in younger adults or with memory performance in either group. CONCLUSIONS: The findings underscore the need to examine brain-behaviour relationships as a function of age. Future studies should include comprehensive assessments in larger lifespan samples to better understand the aging brain.

Optimizing GABAA receptor antagonism for the induction of long-term potentiation in the mouse and rat dentate gyrus in vitro.

The reliable induction of long-term potentiation (LTP) in the dentate gyrus (DG) in vitro requires the blockade of the γ-aminobutyric acid A (GABAA) receptor. In these studies we examined the effectiveness of the specific GABAA receptor antagonist bicuculline methiodide (BMI) in facilitating LTP in the DG from hippocampal slices obtained from either C57Bl/6 mice or Sprague-Dawley rats, two species commonly used for electrophysiology. In the C57Bl/6 mice, maximal short-term potentiation and LTP in the DG were produced with a concentration of 5 µM BMI. In contrast, a concentration of 10 µM BMI was required to produce maximal short-term potentiation and LTP in the DG of Sprague-Dawley rats. These results reveal that there are species differences in the optimal amount of BMI required to produce robust and reliable LTP in the rodent DG in vitro and highlight the need to take consideration of the species being used when choosing concentrations of pharmacological agents to employ for electrophysiological use.NEW & NOTEWORTHY In this report we provide specific neurophysiological evidence for concentrations of GABAA antagonist required to study long-term potentiation in the medial perforant pathway of the dentate gyrus. Two commonly used species, Sprague-Dawley rats and C57Bl/6 mice, require different concentrations of bicuculline methiodide to induce optimal short-term and long-term potentiation.

Active nerve management for above the knee amputation: A comparison of through the wound versus posterior approach.

Targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) are used to prevent or treat neuromas in amputees. TMR for above-the-knee amputation (AKA) is most commonly performed through a posterior incision rather than the stump wound because recipient motor nerves are primarily located in the proximal third of the thigh. When preventative TMR is performed with concurrent AKA, a posterior approach requires intraoperative repositioning and an additional incision. The purpose of this study was to evaluate feasibility of TMR and operative times for nerve management performed through the wound compared to a posterior approach in AKA patients to guide surgical decision-making. Patients who underwent AKA with TMR between 2018-2023 were reviewed. Patients were divided into two groups: TMR performed through the wound (Group I) and TMR performed through a posterior approach (Group II). If a nerve was unable to undergo coaptation for TMR due to the lack of suitable donor motor nerves, RPNI was performed. Eighteen patients underwent AKA with nerve management were included from Group I (8 patients) and Group II (10 patients). TMR coaptations performed on distinct nerves was 1.5 ± 0.5 in Group I compared to 2.6 ± 0.5 in Group II (p = 0.001). Operative time for Group I was 200.7 ± 33.4 min compared to 326.5 ± 37.1 min in Group II (p = 0.001). TMR performed through the wound following AKA requires less operative time than a posterior approach. However, since recipient motor nerves are not consistently found near the stump, RPNI may be required with TMR whereas the posterior approach allows for more TMR coaptations.

Prenatal ethanol and cannabis exposure have sex- and region-specific effects on somatostatin and neuropeptide Y interneurons in the rat hippocampus.

BACKGROUND: Cannabis is increasingly being legalized and socially accepted around the world and is often used with alcohol in social settings. We recently showed that in utero exposure to both substances can alter the density of parvalbumin-expressing interneurons in the hippocampus. Here we investigate the effects of in utero alcohol and cannabis exposure, alone or in combination, on somatostatin- and neuropeptide Y-positive (NPY) interneurons. These are separate classes of interneurons important for network synchrony and inhibition in the hippocampus. METHODS: A 2 (Ethanol, Air) × 2 (tetrahydrocannabinol [THC], Vehicle) design was used to expose pregnant Sprague-Dawley rats to either ethanol or air, in addition to either THC or the inhalant vehicle solution, during gestational days 5-20. Immunohistochemistry for somatostatin- and NPY-positive interneurons was performed in 50 µm tissue sections obtained at postnatal day 70. RESULTS: Exposure to THC in utero had region-specific and sex-specific effects on the density of somatostatin-positive interneurons in the adult rat hippocampus. A female-specific decrease in NPY interneuron cell density was observed in the CA1 region following THC exposure. Combined exposure to alcohol and THC reduced NPY neurons selectively in the ventral dentate gyrus hippocampal subfield. However, overall, co-exposure to alcohol and cannabis had neither additive nor synergistic effects on interneuron populations in other areas of the hippocampus. CONCLUSIONS: These results illustrate how alcohol and cannabis exposure in utero may affect hippocampal function by altering inhibitory processes in a sex-specific manner.

Repeated mild traumatic brain injury causes sex-specific increases in cell proliferation and inflammation in juvenile rats.

Childhood represents a period of significant growth and maturation for the brain, and is also associated with a heightened risk for mild traumatic brain injuries (mTBI). There is also concern that repeated-mTBI (r-mTBI) may have a long-term impact on developmental trajectories. Using an awake closed head injury (ACHI) model, that uses rapid head acceleration to induce a mTBI, we investigated the acute effects of repeated-mTBI (r-mTBI) on neurological function and cellular proliferation in juvenile male and female Long-Evans rats. We found that r-mTBI did not lead to cumulative neurological deficits with the model. R-mTBI animals exhibited an increase in BrdU + (bromodeoxyuridine positive) cells in the dentate gyrus (DG), and that this increase was more robust in male animals. This increase was not sustained, and cell proliferation returning to normal by PID3. A greater increase in BrdU + cells was observed in the dorsal DG in both male and female r-mTBI animals at PID1. Using Ki-67 expression as an endogenous marker of cellular proliferation, a robust proliferative response following r-mTBI was observed in male animals at PID1 that persisted until PID3, and was not constrained to the DG alone. Triple labeling experiments (Iba1+, GFAP+, Brdu+) revealed that a high proportion of these proliferating cells were microglia/macrophages, indicating there was a heightened inflammatory response. Overall, these findings suggest that rapid head acceleration with the ACHI model produces an mTBI, but that the acute neurological deficits do not increase in severity with repeated administration. R-mTBI transiently increases cellular proliferation in the hippocampus, particularly in male animals, and the pattern of cell proliferation suggests that this represents a neuroinflammatory response that is focused around the mid-brain rather than peripheral cortical regions. These results add to growing literature indicating sex differences in proliferative and inflammatory responses between females and males. Targeting proliferation as a therapeutic avenue may help reduce the short term impact of r-mTBI, but there may be sex-specific considerations.

Reelin Rescues Behavioral, Electrophysiological, and Molecular Metrics of a Chronic Stress Phenotype in a Similar Manner to Ketamine.

Over the past decade, ketamine, an NMDA receptor antagonist, has demonstrated fast-acting antidepressant effects previously unseen with monoaminergic-based therapeutics. Concerns regarding psychotomimetic effects limit the use of ketamine for certain patient populations. Reelin, an extracellular matrix glycoprotein, has shown promise as a putative fast-acting antidepressant in a model of chronic stress. However, research has not yet demonstrated the changes that occur rapidly after peripheral reelin administration. To address this key gap in knowledge, male Long-Evans rats underwent a chronic corticosterone (CORT; or vehicle) paradigm (40 mg/kg, 21 d). On day 21, rats were then administered an acute dose of ketamine (10 mg/kg, i.p.), reelin (3 µg, i.v.), or vehicle. Twenty-four hours after administration, rats underwent behavioral or in vivo electrophysiological testing before killing. Immunohistochemistry was used to confirm changes in hippocampal reelin immunoreactivity. Lastly, the hippocampus was microdissected from fresh tissue to ascertain whole cell and synaptic-specific changes in protein expression through Western blotting. Chronic corticosterone induced a chronic stress phenotype in the forced swim test and sucrose preference test (SPT). Both reelin and ketamine rescued immobility and swimming, however reelin alone rescued latency to immobility. In vivo electrophysiology revealed decreases in hippocampal long-term potentiation (LTP) after chronic stress which was increased significantly by both ketamine and reelin. Reelin immunoreactivity in the dentate gyrus paralleled the behavioral and electrophysiological findings, but no significant changes were observed in synaptic-level protein expression. This exploratory research supports the putative rapid-acting antidepressant effects of an acute dose of reelin across behavioral, electrophysiological, and molecular measures.

A Protocol for Remote Cognitive Training Developed for Use in Clinical Populations During the COVID-19 Pandemic.

Many traumatic brain injury (TBI) survivors face scheduling and transportation challenges when seeking therapeutic interventions. The COVID-19 pandemic created a shift in the use of at-home spaces for work, play, and research, inspiring the development of online therapeutic options. In the current study, we determined the feasibility of an at-home cognitive training tool (NeuroTrackerX) that uses anaglyph three-dimensional (3D) glasses and three-dimensional multiple object tracking (3D-MOT) software. We recruited 20 adults (10 female; mean age = 68.3 years, standard deviation [SD] = 6.75) as the at-home training group. We assessed cognitive health status for participants using a self-report questionnaire and the Mini-Mental State Examination (MMSE), and all participants were deemed cognitively healthy (MMSE >26). At-home participants loaned the necessary equipment (e.g., 3D glasses, computer equipment) from the research facilities and engaged in 10 training sessions over 5 weeks (two times per week). Participant recruitment, retention, adherence, and experience were used as markers of feasibility. For program validation, 20 participants (10 female; mean age = 63.39 years, SD = 12.22), who had previously completed at least eight sessions of the in-lab 3D-MOT program, were randomly selected as the control group. We assessed individual session scores, overall improvement, and learning rates between groups. Program feasibility is supported by high recruitment and retention, 90% participant adherence, and participants' ease of use of the program. Validation of the program is supported. Groups showed no differences in session scores (p > 0.05) and percentage improvement (p > 0.05) despite the differences in screen size and 3D technology. Participants in both groups showed significant improvements in task performance across the training sessions (p < 0.001). NeuroTrackerX provides a promising at-home option for cognitive training in cognitively healthy adults and may be a promising avenue as an at-home therapeutic for TBI survivors. This abstract was previously published on clinicaltrials.gov and can be found at: https://www.clinicaltrials.gov/ct2/show/NCT05278273.

Progranulin is an FMRP target that influences macroorchidism but not behaviour in a mouse model of Fragile X Syndrome.

A growing body of evidence has implicated progranulin in neurodevelopment and indicated that aberrant progranulin expression may be involved in neurodevelopmental disease. Specifically, increased progranulin expression in the prefrontal cortex has been suggested to be pathologically relevant in male Fmr1 knockout (Fmr1 KO) mice, a mouse model of Fragile X Syndrome (FXS). Further investigation into the role of progranulin in FXS is warranted to determine if therapies that reduce progranulin expression represent a viable strategy for treating patients with FXS. Several key knowledge gaps remain. The mechanism of increased progranulin expression in Fmr1 KO mice is poorly understood and the extent of progranulin's involvement in FXS-like phenotypes in Fmr1 KO mice has been incompletely explored. To this end, we have performed a thorough characterization of progranulin expression in Fmr1 KO mice. We find that the phenomenon of increased progranulin expression is post-translational and tissue-specific. We also demonstrate for the first time an association between progranulin mRNA and FMRP, suggesting that progranulin mRNA is an FMRP target. Subsequently, we show that progranulin over-expression in Fmr1 wild-type mice causes reduced repetitive behaviour engagement in females and mild hyperactivity in males but is largely insufficient to recapitulate FXS-associated behavioural, morphological, and electrophysiological abnormalities. Lastly, we determine that genetic reduction of progranulin expression on an Fmr1 KO background reduces macroorchidism but does not alter other FXS-associated behaviours or biochemical phenotypes.

An evidence-based review of optimal perioperative practices in minor hand surgery.

BACKGROUND: Like many surgical subspecialties, there have been frequent advancements and discoveries in the field of hand and upper extremity surgery. With a rapidly growing literature base, it can be difficult to remain updated on the latest recommendations. METHODS: A comprehensive literature search was completed on PubMed using MeSH terms. Topics included nutrition management, anticoagulation, immunosuppressive medication management, antibiotic use, skin preparation, splinting, tourniquet use, and suture choice. Data from articles with a level of evidence 1A-3 C were included. RESULTS: A total of 42 articles were identified and reviewed to provide evidence for recommendations regarding various aspects of pre-, intra-, and post-operative care. CONCLUSIONS: The objective of this manuscript is to serve as a resource for evidence-based recommendations by the findings of recent evidence related to perioperative care in elective hand surgery. Additional studies are required in certain areas of the literature in order to provide stronger recommendations.

Revisiting Bipedicled Flaps for Lower Extremity Distal Third Defects.

BACKGROUND: Lower extremity reconstruction of the distal third of the leg is challenging. Free tissue transfer is the criterion standard. The COVID-19 pandemic encouraged seeking alternatives for resource consuming procedures. Bipedicled flaps are flaps with a dual-source subdermal perfusion. The purpose of this study was to assess outcomes of patients who had bipedicled flaps primary or auxiliary local flap for distal third leg/foot reconstruction. METHODS: A retrospective review of patients undergoing lower extremity reconstruction (2020-2021) was performed. Inclusion criteria were patients older than 18 years with lower extremity wounds secondary to traumatic injury for which bipedicled flaps were used in the reconstruction. Exclusion criteria included lower extremity wounds secondary to peripheral vascular disease or diabetes. RESULTS: Fourteen patients were included in the study. All patients had distal third of the leg/foot wounds, and 12 patients (87.5%) had concurrent leg fractures. In 8 patients (57.1%), the bipedicled flap was used to decrease the wound size and facilitate another concurrent flap: hemisoleus (21.4%), anterior tibialis muscle turnover (14.3%), medial plantar artery (14.3%), and posterior tibial artery perforator (14.3%). Mean wound size for bipedicle flaps used alone was 42.0 ± 18.3 cm2, whereas wounds that required a bipedicled flap with an additional flap were 69.9 ± 80.8 cm2 (P = 0.187). Two patients had partial flap necrosis (14.3%) but healed their defect. One patient had nonunion (7.1%). Limb salvage rate was 100%. CONCLUSIONS: Bipedicled flaps can be used as an alternative to free flaps in distal third leg/foot defects in select patients. If distal extremity wounds cannot be covered with a bipedicled flap alone, the flap can be used an accessory flap to facilitate reconstruction with other local flaps.

Stress and traumatic brain injury: An inherent bi-directional relationship with temporal and synergistic complexities.

Traumatic brain injury (TBI) and stress are prevalent worldwide and can both result in life-altering health problems. While stress often occurs in the absence of TBI, TBI inherently involves some element of stress. Furthermore, because there is pathophysiological overlap between stress and TBI, it is likely that stress influences TBI outcomes. However, there are temporal complexities in this relationship (e.g., when the stress occurs) that have been understudied despite their potential importance. This paper begins by introducing TBI and stress and highlighting some of their possible synergistic mechanisms including inflammation, excitotoxicity, oxidative stress, hypothalamic-pituitary-adrenal axis dysregulation, and autonomic nervous system dysfunction. We next describe different temporal scenarios involving TBI and stress and review the available literature on this topic. In doing so we find initial evidence that in some contexts stress is a highly influential factor in TBI pathophysiology and recovery, and vice versa. We also identify important knowledge gaps and suggest future research avenues that will increase our understanding of this inherent bidirectional relationship and could one day result in improved patient care.

Assessing Changes in Synaptic Plasticity Using an Awake Closed-Head Injury Model of Mild Traumatic Brain Injury.

Mild traumatic brain injuries (mTBIs) are a prevalent health issue in North America. There is increasing pressure to utilize ecologically valid models of closed-head mTBI in the preclinical setting to increase translatability to the clinical population. The awake closed-headed injury (ACHI) model uses a modified controlled cortical impactor to deliver closed-headed injury, inducing clinically relevant behavioral deficits without the need for a craniotomy or the use of an anesthetic. This technique does not normally induce fatalities, skull fractures, or brain bleeds, and is more consistent with being a mild injury. Indeed, the mild nature of the ACHI procedure makes it ideal for studies investigating repetitive mTBI (r-mTBI). Growing evidence indicates that r-mTBI can result in a cumulative injury that produces behavioral symptoms, neuropathological changes, and neurodegeneration. r-mTBI is common in youths playing sports, and these injuries occur during a period of robust synaptic reorganization and myelination, making the younger population particularly vulnerable to the long-term influences of r-mTBI. Further, r-mTBI occurs in cases of intimate partner violence, a condition for which there are few objective screening measures. In these experiments, synaptic function was assessed in the hippocampus in juvenile rats that had experienced r-mTBI using the ACHI model. Following the injuries, a tissue slicer was utilized to make hippocampal slices to evaluate bidirectional synaptic plasticity in the hippocampus at either 1 or 7 days following the r-mTBI. Overall, the ACHI model provides researchers with an ecologically valid model to study changes in synaptic plasticity following mTBI and r-mTBI.

Brain changes: aerobic exercise for traumatic brain injury rehabilitation.

Introduction: Traumatic Brain Injury (TBI) accounts for millions of hospitalizations and deaths worldwide. Aerobic exercise is an easily implementable, non-pharmacological intervention to treat TBI, however, there are no clear guidelines for how to best implement aerobic exercise treatment for TBI survivors across age and injury severity. Methods: We conducted a PRISMA-ScR to examine research on exercise interventions following TBI in children, youth and adults, spanning mild to severe TBI. Three electronic databases (PubMed, PsycInfo, and Web of Science) were searched systematically by two authors, using keywords delineated from "Traumatic Brain Injury," "Aerobic Exercise," and "Intervention." Results: Of the 415 papers originally identified from the search terms, 54 papers met the inclusion criteria and were included in this review. The papers were first grouped by participants' injury severity, and subdivided based on age at intervention, and time since injury where appropriate. Discussion: Aerobic exercise is a promising intervention for adolescent and adult TBI survivors, regardless of injury severity. However, research examining the benefits of post-injury aerobic exercise for children and older adults is lacking.

Postnatal Choline Supplementation Rescues Deficits in Synaptic Plasticity Following Prenatal Ethanol Exposure.

Prenatal ethanol exposure (PNEE) is a leading cause of neurodevelopmental impairments, yet treatments for individuals with PNEE are limited. Importantly, postnatal supplementation with the essential nutrient choline can attenuate some adverse effects of PNEE on cognitive development; however, the mechanisms of action for choline supplementation remain unclear. This study used an animal model to determine if choline supplementation could restore hippocampal synaptic plasticity that is normally impaired by prenatal alcohol. Throughout gestation, pregnant Sprague Dawley rats were fed an ethanol liquid diet (35.5% ethanol-derived calories). Offspring were injected with choline chloride (100 mg/kg/day) from postnatal days (PD) 10-30, and then used for in vitro electrophysiology experiments as juveniles (PD 31-35). High-frequency conditioning stimuli were used to induce long-term potentiation (LTP) in the medial perforant path input to the dentate gyrus of the hippocampus. PNEE altered synaptic transmission in female offspring by increasing excitability, an effect that was mitigated with choline supplementation. In contrast, PNEE juvenile males had decreased LTP compared to controls, and this was rescued by choline supplementation. These data demonstrate sex-specific changes in plasticity following PNEE, and provide evidence that choline-related improvements in cognitive functioning may be due to its positive impact on hippocampal synaptic physiology.

Use of Tendon Allograft for Recurrent Extensor Carpi Ulnaris Instability in Ehlers-Danlos Syndrome: A Case Report.

Background Subluxation of the extensor carpi ulnaris (ECU) tendon can be a challenging problem to the surgeon, with no options described for failure following autologous reconstruction. It is our intention to provide guidance on technique by describing our experience in a 20-year-old male with Ehlers-Danlos syndrome. Case Description The patient presented with pain and snapping of the ECU tendon, and failed both immobilization and ECU reconstruction with autologous extensor retinaculum. A gracilis tendon allograft was used to reconstruct the ECU sheath, in addition to ulnar groove deepening. At 1-year follow-up, the patient had no pain and the ECU was stable without recurrent subluxation. Literature Review To the authors' knowledge, the use of tendon allograft for stabilization of recurrent ECU subluxation following surgical repair or reconstruction has not been previously described in the medical literature. Clinical Relevance Utilization of tendon allograft is a viable technique to stabilize the ECU tendon while minimizing the risk in relying on compromised autologous tissue. This report represents the first account of successful reconstruction following failed autologous reconstruction.

Effects of prenatal ethanol exposure on choline-induced long-term depression in the hippocampus.

Choline is an essential nutrient under evaluation as a cognitive enhancing treatment for fetal alcohol spectrum disorders (FASD) in clinical trials. As a result, there is increased pressure to identify therapeutic mechanism(s) of action. Choline is not only a precursor for several essential cell membrane components and signaling molecules but also has the potential to directly affect synaptic mechanisms that are believed important for cognitive processes. In the current work, we study how the direct application of choline can affect synaptic transmission in the dentate gyrus (DG) of hippocampal slices obtained from adolescent (postnatal days 21-28) Sprague-Dawley rats (Rattus norvegicus). The acute administration of choline chloride (2 mM) reliably induced a long-term depression (LTD) of field excitatory postsynaptic potentials (fEPSPs) in the DG in vitro. The depression required the involvement of M1 receptors, and the magnitude of the effect was similar in slices obtained from male and female animals. To further study the impact of choline in an animal model of FASD, we examined offspring from dams fed an ethanol-containing diet (35.5% ethanol-derived calories) throughout gestation. In slices from the adolescent animals that experienced prenatal ethanol exposure (PNEE), we found that the choline induced an LTD that uniquely involved the activation of N-methyl-d-aspartate (NMDA) and M1 receptors. This study provides a novel insight into how choline can modulate hippocampal transmission at the level of the synapse and that it can have unique effects following PNEE.NEW & NOTEWORTHY Choline supplementation is a nutraceutical therapy with significant potential for a variety of developmental disorders; however, the mechanisms involved in its therapeutic effects remain poorly understood. Our research shows that choline directly impacts synaptic communication in the brain, inducing a long-term depression of synaptic efficacy in brain slices. The depression is equivalent in male and female animals, involves M1 receptors in control animals, but uniquely involves NMDA receptors in a model of FASD.

Prenatal alcohol and cannabis exposure can have opposing and region-specific effects on parvalbumin interneuron numbers in the hippocampus.

BACKGROUND: We recently showed that alcohol and cannabis can interact prenatally, and in a recent review paper, we identified parvalbumin-positive (PV) interneurons in the hippocampus as a potential point of convergence for these teratogens. METHODS: A 2 (Ethanol [EtOH], Air) × 2 (tetrahydrocannabinol [THC], Vehicle) design was used to expose pregnant Sprague-Dawley rats to either EtOH or air, in addition to either THC or the inhalant vehicle solution, during gestational days 5-20. Immunohistochemistry was performed to detect PV interneurons in 1 male and 1 female pup from each litter at postnatal day 70. RESULTS: Significant between-group and subregion-specific effects were found in the dorsal cornu ammonis 1 (CA1) subfield and the ventral dentate gyrus (DG). In the dorsal CA1 subfield, there was an increase in the number of PV interneurons in both the EtOH and EtOH +THC groups, but a decrease with THC alone. There were fewer changes in interneuron numbers overall in the DG, though there was a sex difference, with a decrease in the number of PV interneurons in the THC-exposed group in males. There was also a greater cell layer volume in the DG in the EtOH +THC group than the control group, and in the CA1 region in the EtOH group compared to the control and THC groups. CONCLUSIONS: Prenatal exposure to alcohol and THC differentially affects parvalbumin-positive interneuron numbers in the hippocampus, indicating that both individual and combined exposure can impact the balance of excitation and inhibition in a structure critically involved in learning and memory processes.