Prenatal Opioid Exposure Impairs Endocannabinoid and Glutamate Transmission in the Dorsal Striatum

Abstract

The opioid crisis has contributed to a growing population of children exposed to opioids during fetal development; however, many of the long-term effects of opioid exposure on development are unknown. We previously demonstrated that opioids have deleterious effects on endocannabinoid plasticity at glutamate synapses in the dorsal striatum of adolescent rodents, but it is unclear whether prenatal opioid exposure produces similar neuroadaptations. Using a mouse model of prenatal methadone exposure (PME), we performed proteomics, phosphoproteomics, and patch-clamp electrophysiology in the dorsolateral striatum (DLS) and dorsomedial striatum (DMS) to examine synaptic functioning in adolescent PME offspring. PME impacted the proteome and phosphoproteome in a region- and sex-dependent manner. Many proteins and phosphorylated proteins associated with glutamate transmission were differentially abundant in PME offspring, which was associated with reduced glutamate release in the DLS and altered the rise time of excitatory events in the DMS. Similarly, the intrinsic excitability properties of DMS neurons were significantly affected by PME. Last, pathway analyses revealed an enrichment in retrograde endocannabinoid signaling in the DLS, but not in the DMS, of males. Electrophysiology studies confirmed that endocannabinoid-mediated synaptic depression was impaired in the DLS, but not DMS, of PME-males. These results indicate that PME induces persistent neuroadaptations in the dorsal striatum and could contribute to the aberrant behavioral development described in offspring with prenatal opioid exposure.

Alterations of brain microstructures in a mouse model of prenatal opioid exposure detected by diffusion MRI

“…We and others have described delayed development of several sensorimotor-based developmental milestones including the cliff aversion, surface righting, and forelimb grasp task, among others, which suggest opioid exposed offspring may lack the ability to translate multimodal sensory input into complex motor behaviors 21 , 63 – 65 . Furthermore, we have also demonstrated that PME disrupts synaptic signaling in the somatosensory cortex, motor cortex and dorsal striatum using brain slice, patch-clamp electrophysiology 21 , 26 , 27 . Therefore, these changes in diffusion tensor and neurite dispersion metrics may reflect alterations in synaptic architecture related to our observed differences in synaptic transmission in PME offspring.…”

“…We note that in our prior behavioral study of sensorimotor development we did not observe many significant sex differences 21 . However, additional work from our laboratory using this model have revealed behavioral, physiological, and biochemical sex differences [25][26][27] . Future work will need to examine female offspring to confirm findings or explore sex-effects in neuroimaging.…”

“…Furthermore, ultra-high field structural MRI did not reveal any differences in various cortical and subcortical grey matter volumes suggesting the effects of our PME model may impact more terminal process of neurodevelopment such as axonogenesis and dendritogenesis which would not be identified by cell density or volumetric MRI assessments 21 . Indeed, when examining large-scale proteomic and phosphoproteomic data in the dorsal striatum and somatosensory cortex of PME male offspring, we discovered an enrichment in proteins/phosphopeptides associated with the axonal and dendritic cellular compartment and proteins/phosphopeptides which function in axonal guidance, the maintenance of synaptic architecture, and NGF-mediated transcription 26,27 . Similarly, other models of prenatal opioid exposure have identified differences in the expression of various growth factors and their receptors such as NGF and BDNF which are known to be involved in axonal growth and dendritic branching [79][80][81][82] .…”

“…We have discovered that PME disrupts early neurobehavioral developmental milestones, produces hyperactivity, and alters reward-related behavior in mouse offspring 21,25 . Additionally, offspring demonstrate altered neuronal excitability and synaptic signaling in the motor cortex, somatosensory cortex, and the dorsal striatum (analogous to the human caudate/putamen) that persists into early adolescence which is likely to contribute to the aberrant behavioral development in PME offspring 21,[25][26][27] .…”

Prenatal methadone exposure selectively alters protein expression in primary motor cortex: implications for synaptic function

“…The potential neural mechanisms that mediate the sensorimotor deficits and hyperactivity observed in our model are diverse. We previously characterized PME-induced physiological and biochemical changes in the dorsal striatum, a brain region that integrates input from sensorimotor cortices (Grecco, Munoz et al 2022). We have also described the effects of PME on the biochemical, anatomical and electrophysiological properties of the primary somatosensory cortex (S1) (Grecco, Huang et al 2022).…”