PTEN Loss Increases the Connectivity of Fast Synaptic Motifs and Functional Connectivity in a Developing Hippocampal Network

Abstract

Changes in synaptic strength and connectivity are thought to be a major mechanism through which many gene variants cause neurological disease. Hyperactivation of the PI3K-mTOR signaling network, via loss of function of repressors such as PTEN, causes epilepsy in humans and animal models, and altered mTOR signaling may contribute to a broad range of neurological diseases. Changes in synaptic transmission have been reported in animal models of PTEN loss; however, the full extent of these changes, and their effect on network function, is still unknown. To better understand the scope of these changes, we recorded from pairs of mouse hippocampal neurons cultured in a two-neuron microcircuit configuration that allowed us to characterize all four major connection types within the hippocampus. Loss of PTEN caused changes in excitatory and inhibitory connectivity, and these changes were postsynaptic, presynaptic, and transynaptic, suggesting that disruption of PTEN has the potential to affect most connection types in the hippocampal circuit. Given the complexity of the changes at the synaptic level, we measured changes in network behavior after deleting Pten from neurons in an organotypic hippocampal slice network. Slices containing Pten-deleted neurons showed increased recruitment of neurons into network bursts. Importantly, these changes were not confined to Pten-deleted neurons, but involved the entire network, suggesting that the extensive changes in synaptic connectivity rewire the entire network in such a way that promotes a widespread increase in functional connectivity.

Glutamatergic Innervation onto Striatal Neurons Potentiates GABAergic Synaptic Output

“…1). This finding partially agrees with previous studies in the hippocampus (Chang et al, 2014;Barrows et al, 2017) that reported an increase in GABAergic output upon glutamatergic innervation, suggesting a more general role of glutamatergic input in modulating the degree of inhibition produced by GABAergic neurons. Nevertheless, the modulation by glutamatergic input in the different types of GABAergic neurons manifests in different ways: hippocampal interneurons increased the number of their output synapses, but decreased the presynaptic release efficiency (Chang et al, 2014), whereas striatal GABAergic neurons increased their evoked inhibitory response and vesicle pool size, while maintaining their release efficiency (Fig.…”

Altered Fast Synaptic Transmission in a Mouse Model of DNM1-Associated Developmental Epileptic Encephalopathy

“…A previous imaging study of Dnm1/3 DKO neurons found severely reduced event frequency (Lou et al, 2012), thus, the Dnm1 Ftfl/Ftfl phenotype may represent a milder version of the Dnm1/3 DKO. Other in vitro networks of neurons from DEE-causing gene variants, including Scn1a (Hedrich et al, 2014), GNB1 (Colombo et al, 2019), Kcnt1 (Shore et al, 2020), and Pten (Barrows et al, 2017), have shown increases in activity and/or synchrony, as measured with Ca 2+ imaging or multielectrode arrays. Our results suggest, however, that in Dnm1 Ftfl/Ftfl networks at least, higher order levels of brain architecture are necessary to generate epileptic activity.…”

Conditional Pten knockout in parvalbumin- or somatostatin-positive neurons sufficiently leads to autism-related behavioral phenotypes

“…At the synaptic level, conditional knockout Pten from GABAergic cortical interneurons increases the synaptic input onto interneurons [ 74 ] and the inhibitory output onto glutamatergic neurons [ 22 , 75 ]. Conversely, a single copy of Pten deletion from PV-neurons impairs the formation of perisomatic inhibition [ 76 ].…”