Dataset Information

Role of matrix metalloproteinase-9 in neurodevelopmental deficits and experience-dependent plasticity in Xenopus laevis.

ABSTRACT: Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 may also lead to neurodevelopmental disorders (ND). Here, we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed in Xenopus tadpoles after early exposure to valproic acid (VPA), a known teratogen associated with ND in humans. In Xenopus tadpoles, VPA exposure results in excess local synaptic connectivity, disrupted social behavior and increased seizure susceptibility. We found that overexpressing MMP-9 in the brain copies effects of VPA on synaptic connectivity, and blocking MMP-9 activity pharmacologically or genetically reverses effects of VPA on physiology and behavior. We further show that during normal neurodevelopment MMP-9 levels are tightly regulated by neuronal activity and required for structural plasticity. These studies show a critical role for MMP-9 in both normal and abnormal development.

SUBMITTER: Gore SV

PROVIDER: S-EPMC8315794 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Role of matrix metalloproteinase-9 in neurodevelopmental deficits and experience-dependent plasticity in <i>Xenopus laevis</i>.

Gore Sayali V SV James Eric J EJ Huang Lin-Chien LC Park Jenn J JJ Berghella Andrea A Thompson Adrian C AC Cline Hollis T HT Aizenman Carlos D CD

eLife 20210720

Matrix metalloproteinase-9 (MMP-9) is a secreted endopeptidase targeting extracellular matrix proteins, creating permissive environments for neuronal development and plasticity. Developmental dysregulation of MMP-9 may also lead to neurodevelopmental disorders (ND). Here, we test the hypothesis that chronically elevated MMP-9 activity during early neurodevelopment is responsible for neural circuit hyperconnectivity observed in <i>Xenopus</i> tadpoles after early exposure to valproic acid (VPA), ...[more]

PMID: 34282726

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Project description:Communication between optic tecta/superior colliculi is thought to be required for sensorimotor behaviors by comparing inputs across the midline, however the development of and the role of visual experience in the function and plasticity of intertectal connections are unclear. We combined neuronal tracing, in vivo time-lapse imaging, and electrophysiology to characterize the structural and functional development of intertectal axons and synapses in Xenopus tadpole optic tectum. We find that intertectal connections are established early during optic tectal circuit development. We determined the neurotransmitter identity of intertectal neurons using both rabies virus-mediated tracing combined with post-hoc immunohistochemistry, and electrophysiology. Excitatory and inhibitory intertectal neuronal somata are similarly distributed throughout the tectum. Excitatory and inhibitory intertectal axons are structurally similar and elaborate broadly in the contralateral tectum. We demonstrate that intertectal and retinotectal axons converge onto tectal neurons by recording postsynaptic currents after stimulating intertectal and retinotectal inputs. Cutting the intertectal commissure removes synaptic responses to contralateral tectal stimulation. In vivo time-lapse imaging demonstrated that visual experience drives plasticity in intertectal bouton size and dynamics. Finally, visual experience coordinately drives the maturation of excitatory and inhibitory intertectal inputs by increasing AMPA- and GABA-receptor mediated currents, comparable to experience-dependent maturation of retinotectal inputs. These data indicate that visual experience regulates plasticity of excitatory and inhibitory intertectal inputs, maintaining the excitatory: inhibitory ratio of intertectal input. These studies place intertectal inputs as key players in tectal circuit development and suggest that they may play a role in sensory information processing critical to sensorimotor behaviors.

Project description:The hippocampus forms memories of our experiences by registering processed sensory information in coactive populations of excitatory principal cells or ensembles1-3. Fast-spiking parvalbumin-expressing inhibitory neurons (PV INs) in the dentate gyrus (DG)-CA3/CA2 circuit contribute to memory encoding by exerting precise temporal control of excitatory principal cell activity through mossy fiber-dependent feed-forward inhibition4-13. PV INs respond to input-specific information by coordinating changes in their intrinsic excitability, input-output synaptic-connectivity, synaptic-physiology and synaptic-plasticity9,13-17, referred to here as experience-dependent PV IN plasticity, to influence hippocampal functions. PV IN impairments in early life, when neural circuitry is highly sensitive to experience-dependent refinement, are thought to result in imbalanced excitation and inhibition, impaired cognition, network hyperexcitability and seizures: hallmarks of neurodevelopmental disorders (NDDs) such as Autism Spectrum Disorder and epilepsy18-20. Discovery of transcriptional regulators of experience-dependent PV IN plasticity in the adult hippocampus may permit reversal of these developmental impairments. Here, in a screen designed to capture the PV IN intrinsic program induced by increased mossy fiber inputs, a trigger for experience-dependent PV IN plasticity, we identify the homeobox gene Meis2 21 as a regulator of experience-dependent PV IN plasticity gene (XPG) in the adult DG-CA3/CA2 circuit. We found that a significant number of upregulated XPGs also exhibit haploinsufficiency in ASDs, epilepsies, and schizophrenia. We demonstrate that virally-mediated rescue of experience-dependent Meis2 upregulation in CA3/CA2 PV INs in a NDD risk mouse model in adulthood is sufficient to restore experience-dependent PV IN plasticity, spatial and social memory, ensemble specificity, suppression of network hyperexcitability and seizures. Together, these findings suggest that experience-dependent PV IN plasticity is a convergent mechanism for NDD risk genes that can be re-instated in adulthood to reverse developmental deficits in circuitry, network excitability and cognition.

Dataset Information

Role of matrix metalloproteinase-9 in neurodevelopmental deficits and experience-dependent plasticity in Xenopus laevis.

Publications

Role of matrix metalloproteinase-9 in neurodevelopmental deficits and experience-dependent plasticity in <i>Xenopus laevis</i>.

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