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Identifier

000425505

Title

Functional and cellular analysis of cortical neurons during early postnatal period in genetic modified mice.

Alternative Title

Λειτουργική και μορφολογική ανάλυση μυών με γενετικά τροποποιημένους πληθυσμούς του φλοιού των εγκεφαλικών ημισφαιρίων.

Author

Καλεμάκη, Αικατερίνη

Thesis advisor

Καραγωγέως, Δόμνα

Reviewer

Σιδηροπούλου, Κυριακή
Μαυροθαλασσίτης, Γεώργιος

Abstract

Developmental changes in early postnatal inhibitory circuits in the medial prefrontal cortex compared to primary somatosensory cortex of the mouse. The prefrontal cortex (PFC) controls higher cognitive abilities severely impaired in neurodevelopmental disorders. The PFC is characterised by delayed maturation extending until the end of adolescence. The cellular mechanisms controlling the early development of prefrontal circuits are still largely unresolved. Our study delineates the developmental cellular processes in vitro that are on-going in the mouse medial PFC (mPFC) during the second and third postnatal weeks (P10 and P20) or neonatal and pre-juvenile periods, respectively, and compares them to those in the barrel cortex (BC). We show that the basal synaptic transmission decreases with age as a result of a concurrent reduction of spontaneous postsynaptic excitatory currents and increase of inhibitory ones. Although total cell density in the mPFC is decreased from the second to third postnatal week, the number of parvalbumin (PV) and serotonin receptor (5HT3aR)-positive interneurons is increased. Furthermore, our data indicate that increased GABAA receptor activity leads to increased basal synaptic transmission of neonatal mPFC, showing that the effect of GABA is not inhibitory in this time window in mPFC in contrast to BC. Supporting evidence comes form results describing the expression of KCC2, an integral transporter involved in the switch between depolarizing and hyperpolarizing action of GABA. KCC2 levels are decreased in neonatal mPFC compared to both pre-juvenile PFC and BC at both ages. In parallel, the intrinsic properties of both interneurons and pyramidal are altered from P10 to P20 in both brain areas. Finally, we show that all the above developmental events relate to increased network activity in the mPFC from the second to the third postnatal week, in vivo. Mice with decreased number of interneurons exhibit aberrant spontaneous and oscillatory activity in the barrel cortex. GABAergic (γ-aminobutyric acid) neurons are inhibitory neurons and protect neural tissue from excessive excitation. Cortical GABAergic neurons play a pivotal role for the generation of synchronized cortical network oscillations. Imbalance between excitatory and inhibitory mechanisms underlies many neuropsychiatric disorders and is correlated with abnormalities in oscillatory activity, especially in the gamma frequency range (30-80Hz). We investigated the functional changes in cortical network activity in response to developmentally reduced inhibition in the adult mouse barrel cortex (BC). We used a mouse model that displays ~50% fewer cortical interneurons due to the loss of Rac1 protein from Nkx2.1/Cre-expressing cells (Rac1 conditional knockout (cKO) mice), to examine how this developmental loss of cortical interneurons may affect basal synaptic transmission, synaptic plasticity, spontaneous activity and neuronal oscillations in the adult BC. The decrease in the number of interneurons increased basal synaptic transmission, as examined by recording field excitatory postsynaptic potentials (fEPSPs) from layer II networks in the Rac1 cKO mouse cortex, decreased long-term potentiation (LTP) in response to tetanic stimulation but did not alter the pair-pulse ratio (PPR). Furthermore, under spontaneous recording conditions, Rac1 cKO brain slices exhibit enhanced sensitivity and susceptibility to emergent spontaneous activity. We also found that this developmental decrease in the number of cortical interneurons results in local neuronal networks with alterations in neuronal oscillations, exhibiting decreased power in low frequencies (delta, theta, alpha) and gamma frequency range (30-80Hz) with an extra aberrant peak in high gamma frequency range (80-150Hz). Therefore, our data show that disruption in GABAergic inhibition alters synaptic properties and plasticity, while it additionally disrupts the cortical neuronal synchronization in the adult BC.

Language

English

Subject

Barrel cortex

Oscillation

Prefrontal cortex

Βαρελοειδής φλοιός

Προμετωπιαίος φλοιός

Πρώιμη μεταγεννετική περίοδο

Ρυθμική δραστηριότητα

Issue date

2019-12-11