scholarly journals Reduced hippocampal inhibition and enhanced autism-epilepsy comorbidity in mice lacking neuropilin 2

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Carol Eisenberg ◽  
Deepak Subramanian ◽  
Milad Afrasiabi ◽  
Patryk Ziobro ◽  
Jack DeLucia ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Resting Membrane Potential ◽  
Behavioral Deficits ◽  
Ca1 Pyramidal Neurons ◽  
Neuronal Processes ◽  
And Migration ◽  
Y Cells ◽  
Circuit Function ◽  
Deficient Mice

AbstractThe neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2-deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2−/− mice have a reduced number of parvalbumin, somatostatin, and neuropeptide Y cells, mainly in CA1. Whole-cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/− and Nrp2−/− mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2-deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration, and higher severity in Nrp2−/− compared to Nrp2+/+ animals. Finally, Nrp2+/− and Nrp2−/− but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2−/− mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

scholarly journals Reduced Hippocampal Inhibition and Enhanced Autism-Epilepsy Comorbidity in Mice Lacking Neuropilin 2

2021 ◽  
Author(s):  
Carol Eisenberg ◽  
Deepak Subramanian ◽  
Milad Afrasiabi ◽  
Patryk Ziobro ◽  
Jack DeLucia ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Resting Membrane Potential ◽  
Behavioral Deficits ◽  
Ca1 Pyramidal Neurons ◽  
Neuronal Processes ◽  
And Migration ◽  
Y Cells ◽  
Circuit Function ◽  
Deficient Mice

The neuropilin receptors and their secreted semaphorin ligands play key roles in brain circuit development by regulating numerous crucial neuronal processes, including the maturation of synapses and migration of GABAergic interneurons. Consistent with its developmental roles, the neuropilin 2 (Nrp2) locus contains polymorphisms in patients with autism spectrum disorder (ASD). Nrp2 deficient mice show autism-like behavioral deficits and propensity to develop seizures. In order to determine the pathophysiology in Nrp2 deficiency, we examined the hippocampal numbers of interneuron subtypes and inhibitory regulation of hippocampal CA1 pyramidal neurons in mice lacking one or both copies of Nrp2. Immunostaining for interneuron subtypes revealed that Nrp2-/- mice have reduced number of parvalbumin, somatostatin and Neuropeptide Y cells, mainly in CA1. Whole cell recordings identified reduced firing and hyperpolarized shift in resting membrane potential in CA1 pyramidal neurons from Nrp2+/- and Nrp2-/- mice compared to age-matched wild-type controls indicating decrease in intrinsic excitability. Simultaneously, the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) are reduced in Nrp2 deficient mice. A convulsive dose of kainic acid evoked electrographic and behavioral seizures with significantly shorter latency, longer duration and higher severity in Nrp2-/- compared to Nrp2+/+ animals. Finally, Nrp2+/- and Nrp2-/-, but not Nrp2+/+, mice have impaired cognitive flexibility demonstrated by reward-based reversal learning, a task associated with hippocampal circuit function. Together these data demonstrate a broad reduction in interneuron subtypes and compromised inhibition in CA1 of Nrp2-/- mice, which could contribute to the heightened seizure susceptibility and behavioral deficits consistent with an ASD/epilepsy phenotype.

scholarly journals Synergistic inhibition of histone modifiers produces therapeutic effects in adult Shank3-deficient mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Freddy Zhang ◽  
Benjamin Rein ◽  
Ping Zhong ◽  
Treefa Shwani ◽  
Megan Conrow-Graham ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Social Preference ◽  
Intervention Strategy ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Pharmacological Intervention ◽  
Therapeutic Effects ◽  
Male Mice ◽  
Behavioral Abnormalities ◽  
Deficient Mice

AbstractAutism spectrum disorder (ASD) is a lifelong developmental disorder characterized by social deficits and other behavioral abnormalities. Dysregulation of epigenetic processes, such as histone modifications and chromatin remodeling, have been implicated in ASD pathology, and provides a promising therapeutic target for ASD. Haploinsufficiency of the SHANK3 gene is causally linked to ASD, so adult (3–5 months old) Shank3-deficient male mice were used in this drug discovery study. We found that combined administration of the class I histone deacetylase inhibitor Romidepsin and the histone demethylase LSD1 inhibitor GSK-LSD1 persistently ameliorated the autism-like social preference deficits, while each individual drug alone was largely ineffective. Another behavioral abnormality in adult Shank3-deficient male mice, heightened aggression, was also alleviated by administration of the dual drugs. Furthermore, Romidepsin/GSK-LSD1 treatment significantly increased transcriptional levels of NMDA receptor subunits in prefrontal cortex (PFC) of adult Shank3-deficient mice, resulting in elevated synaptic expression of NMDA receptors and the restoration of NMDAR synaptic function in PFC pyramidal neurons. These results have offered a novel pharmacological intervention strategy for ASD beyond early developmental periods.

scholarly journals Hippocampal CA1 Pyramidal Neurons ofMecp2Mutant Mice Show a Dendritic Spine Phenotype Only in the Presymptomatic Stage

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Christopher A. Chapleau ◽  
Elena Maria Boggio ◽  
Gaston Calfa ◽  
Alan K. Percy ◽  
Maurizio Giustetto ◽  
...  
Keyword(s):  
Dendritic Spines ◽  
Dendritic Spine ◽  
Pyramidal Neurons ◽  
Mutant Mice ◽  
Spine Density ◽  
Ca1 Pyramidal Neurons ◽  
Dendritic Spine Density ◽  
Presymptomatic Stage ◽  
Deficient Mice

Alterations in dendritic spines have been documented in numerous neurodevelopmental disorders, including Rett Syndrome (RTT). RTT, an X chromosome-linked disorder associated with mutations inMECP2, is the leading cause of intellectual disabilities in women. Neurons inMecp2-deficient mice show lower dendritic spine density in several brain regions. To better understand the role of MeCP2 on excitatory spine synapses, we analyzed dendritic spines of CA1 pyramidal neurons in the hippocampus ofMecp2tm1.1Jaemale mutant mice by either confocal microscopy or electron microscopy (EM). At postnatal-day 7 (P7), well before the onset of RTT-like symptoms, CA1 pyramidal neurons from mutant mice showed lower dendritic spine density than those from wildtype littermates. On the other hand, at P15 or later showing characteristic RTT-like symptoms, dendritic spine density did not differ between mutant and wildtype neurons. Consistently, stereological analyses at the EM level revealed similar densities of asymmetric spine synapses in CA1stratum radiatumof symptomatic mutant and wildtype littermates. These results raise caution regarding the use of dendritic spine density in hippocampal neurons as a phenotypic endpoint for the evaluation of therapeutic interventions in symptomaticMecp2-deficient mice. However, they underscore the potential role of MeCP2 in the maintenance of excitatory spine synapses.

scholarly journals Parvalbumin interneuron dysfunction in a thalamus - prefrontal cortex circuit in Disc1 deficiency mice

2016 ◽  
Author(s):  
Kristen Delevich ◽  
Hanna Jaaro-Peled ◽  
Mario Penzo ◽  
Akira Sawa ◽  
Bo Li
Keyword(s):  
Prefrontal Cortex ◽  
Mouse Models ◽  
Pyramidal Neurons ◽  
Neural Circuit ◽  
Gaba Release ◽  
Parvalbumin Interneurons ◽  
Parvalbumin Interneuron ◽  
Inhibitory Circuit ◽  
Circuit Function ◽  
Deficient Mice

AbstractTwo of the most consistent findings across disrupted-in-schizophrenia-1 (DISC1) mouse models are impaired working memory and reduced number or function of parvalbumin interneurons within the prefrontal cortex. While these findings suggest parvalbumin interneuron dysfunction in DISC1-related pathophysiology, to date, cortical inhibitory circuit function has not been investigated in depth in DISC1 deficiency mouse models. Here we assessed the function of a feedforward circuit between the mediodorsal thalamus (MD) and the medial prefrontal cortex (mPFC) in mice harboring a deletion in one allele of the Disc1 gene. We found that the inhibitory drive onto layer 3 pyramidal neurons in the mPFC was significantly reduced in the Disc1 deficient mice. This reduced inhibition was accompanied by decreased GABA release from local parvalbumin, but not somatostatin, inhibitory interneurons, and by impaired feedforward inhibition in the MD-mPFC circuit. Our results reveal a cellular mechanism by which deficiency in DISC1 causes neural circuit dysfunction frequently implicated in psychiatric disorders.

scholarly journals Neuroligin3 splice isoforms shape inhibitory synaptic function in the mouse hippocampus

2020 ◽  
Vol 295 (25) ◽  
pp. 8589-8595 ◽  
Author(s):  
Motokazu Uchigashima ◽  
Ming Leung ◽  
Takuya Watanabe ◽  
Amy Cheung ◽  
Timmy Le ◽  
...  
Keyword(s):  
Synaptic Transmission ◽  
Single Cell ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Synaptic Function ◽  
Synaptic Activity ◽  
Dependent Manner ◽  
Splice Isoforms ◽  
Inhibitory Synaptic Transmission ◽  
Ca1 Pyramidal Neurons

Synapse formation is a dynamic process essential for the development and maturation of the neuronal circuitry in the brain. At the synaptic cleft, trans-synaptic protein–protein interactions are major biological determinants of proper synapse efficacy. The balance of excitatory and inhibitory synaptic transmission (E-I balance) stabilizes synaptic activity, and dysregulation of the E-I balance has been implicated in neurodevelopmental disorders, including autism spectrum disorders. However, the molecular mechanisms underlying the E-I balance remain to be elucidated. Here, using single-cell transcriptomics, immunohistochemistry, and electrophysiology approaches to murine CA1 pyramidal neurons obtained from organotypic hippocampal slice cultures, we investigate neuroligin (Nlgn) genes that encode a family of postsynaptic adhesion molecules known to shape excitatory and inhibitory synaptic function. We demonstrate that the NLGN3 protein differentially regulates inhibitory synaptic transmission in a splice isoform–dependent manner at hippocampal CA1 synapses. We also found that distinct subcellular localizations of the NLGN3 isoforms contribute to the functional differences observed among these isoforms. Finally, results from single-cell RNA-Seq analyses revealed that Nlgn1 and Nlgn3 are the major murine Nlgn genes and that the expression levels of the Nlgn splice isoforms are highly diverse in CA1 pyramidal neurons. Our results delineate isoform-specific effects of Nlgn genes on the E-I balance in the murine hippocampus.

scholarly journals TRPM4 Expression During Postnatal Developmental of Mouse CA1 Pyramidal Neurons

2021 ◽  
Vol 15 ◽  
Author(s):  
Denise Riquelme ◽  
Oscar Cerda ◽  
Elias Leiva-Salcedo
Keyword(s):  
Membrane Potential ◽  
Patch Clamp ◽  
Postnatal Development ◽  
Pyramidal Neurons ◽  
Brain Slices ◽  
Long Term Potentiation ◽  
Neuronal Firing ◽  
Resting Membrane Potential ◽  
Ca1 Pyramidal Neurons ◽  
Apical Dendrites

TRPM4 is a non-selective cation channel activated by intracellular calcium and permeable to monovalent cations. This channel participates in the control of neuronal firing, neuronal plasticity, and neuronal death. TRPM4 depolarizes dendritic spines and is critical for the induction of NMDA receptor-dependent long-term potentiation in CA1 pyramidal neurons. Despite its functional importance, no subcellular localization or expression during postnatal development has been described in this area. To examine the localization and expression of TRPM4, we performed duplex immunofluorescence and patch-clamp in brain slices at different postnatal ages in C57BL/6J mice. At P0 we found TRPM4 is expressed with a somatic pattern. At P7, P14, and P35, TRPM4 expression extended from the soma to the apical dendrites but was excluded from the axon initial segment. Patch-clamp recordings showed a TRPM4-like current active at the resting membrane potential from P0, which increased throughout the postnatal development. This current was dependent on intracellular Ca2+ (ICAN) and sensitive to 9-phenanthrol (9-Ph). Inhibiting TRPM4 with 9-Ph hyperpolarized the membrane potential at P14 and P35, with no effect in earlier stages. Together, these results show that TRPM4 is expressed in CA1 pyramidal neurons in the soma and apical dendrites and associated with a TRPM4-like current, which depolarizes the neurons. The expression, localization, and function of TRPM4 throughout postnatal development in the CA1 hippocampal may underlie an important mechanism of control of membrane potential and action potential firing during critical periods of neuronal development, particularly during the establishment of circuits.

Altered balance between excitatory and inhibitory inputs onto CA1 pyramidal neurons from SV2A-deficient but not SV2B-deficient mice

2012 ◽  
Vol 90 (12) ◽  
pp. 2317-2327 ◽  
Author(s):  
Kumar Venkatesan ◽  
Philippe Alix ◽  
Alice Marquet ◽  
Melissa Doupagne ◽  
Isabelle Niespodziany ◽  
...  
Keyword(s):  
Pyramidal Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Deficient Mice

scholarly journals Selective Postnatal Excitation of Neocortical Pyramidal Neurons Results in Distinctive Behavioral and Circuit Deficits in Adulthood

2020 ◽  
Author(s):  
William E. Medendorp ◽  
Akash Pal ◽  
Madison Waddell ◽  
Andreas Björefeldt ◽  
Christopher I. Moore ◽  
...  
Keyword(s):  
Experimental Approach ◽  
Pyramidal Neurons ◽  
Autism Spectrum ◽  
Inhibitory Neurons ◽  
Neocortical Neurons ◽  
And Function ◽  
Circuit Function ◽  
And Behavior ◽  
The Impact

SummaryIn leading models of Autism Spectrum Disorder, and in human data, the efficacy of outgoing cortical connectivity transitions from overly exuberant to languid from early development to adulthood. This transition begs the question of whether the early enhancement in excitation might be a common driver, across etiologies, of these symptoms. We directly tested this concept by chemogenetically driving neuronal activity in neocortical neurons during postnatal days 4-14. Hyperexcitation of Emx1-, but not dopamine transporter-, parvalbumin-, or Dlx5/6-expressing neurons led to decreased social interaction and increased grooming activity in adult animals. In vivo optogenetic interrogation in adults revealed decreased baseline but increased stimulus-evoked firing rates of pyramidal neurons, impaired recruitment of inhibitory neurons and reduced cortico-striatal communication. These results directly support the prediction that changed firing in developing circuits irreversibly alters adult circuit function that leads to maladaptive changes in behaviors. This experimental approach offers a valuable platform to study the impact of disruption of developmental neural activity on the formation and function of adult neural circuits and behavior.

scholarly journals Experience-dependent changes in hippocampal spatial activity and hippocampal circuit function are disrupted in a rat model of Fragile X Syndrome

2021 ◽  
Author(s):  
Antonis Asiminas ◽  
Sam A Booker ◽  
Owen R Dando ◽  
Zrinko Kozic ◽  
Daisy Arkell ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
Rat Model ◽  
Pyramidal Neurons ◽  
Fragile X ◽  
Autism Spectrum ◽  
Oscillatory Activity ◽  
Ca1 Neurons ◽  
Ca1 Pyramidal Neurons ◽  
Spatial Tuning ◽  
Cognitive Inflexibility

Fragile X syndrome (FXS) is a common single gene cause of intellectual disability and Autism Spectrum Disorder. Cognitive inflexibility is one of the hallmarks of FXS, with affected individuals showing extreme difficulty adapting to novel or complex situations. To explore the neural correlates of this cognitive inflexibility, we used a rat model of FXS (Fmr1 KO), and recorded from the CA1 region of the hippocampus while animals habituated in a novel environment for two consecutive days. On the first day of exploration, the firing rate and spatial tuning of CA1 pyramidal neurons was similar between wild-type (WT) and Fmr1 KO rats. However, while CA1 pyramidal neurons from WT rats showed experience-dependent changes in firing and spatial tuning between the first and second day of exposure to the environment, these changes were decreased or absent in CA1 neurons of Fmr1 KO rats. These findings were consistent with increased excitability of Fmr1 KO CA1 neurons in ex-vivo hippocampal slices, which correlated with reduced synaptic inputs from the medial entorhinal cortex. Lastly, activity patterns of CA1 pyramidal neurons were discoordinated with respect to hippocampal oscillatory activity in Fmr1 KO rats. These findings suggest a network-level origin of cognitive deficits in FXS.

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