Research overview

Development of neuronal circuits involves a period during which synaptic connectivity is dynamically refined to its adult functions in an activity-dependent manner. During this early development, immature neuronal networks are highly susceptible for Hebbian and homeostatic plasticity, which is instrumental for the development of the circuitry, but also makes them highly vulnerable to disturbance.

We aim to understand the synaptic mechanisms that facilitate structural and functional plasticity in the developing circuits, focusing on glutamate-receptor mediated signaling in the hippocampus and amygdala. In addition, we are interested to understand how malfunction of these early plasticity mechanisms influences wiring of the limbic networks and increase vulnerability to neuropsychiatric disorders later on in life. In this context, we are particularly interested in the effects of early life stress. 

Our experimental approach involves the use of electrophysiological techniques in combination with pharmacological and local genetic manipulation in various neuronal preparations.

Development of limbic neural circuits is regulated by kainate-type glutamate receptors 

Kainate receptors (KARs), together with AMPA and NMDA receptors, belong to the family of ionotropic glutamate receptors. We and others have shown that KARs have unique developmentally restricted functions that are downregulated in parallel with maturation of the circuitry (for review, see Lauri et al., 2021). These immature-type KAR functions are critical for activity –dependent refinement of the synaptic circuitry, both in the hippocampus and in the amygdala. 

Ryazantseva et al. (2020) Kainate receptors regulate development of glutamatergic synaptic circuitry in the rodent amygdala Elife. 9:e52798. 

Haikonen et al. (2024) GluK1 kainate receptors are necessary for functional maturation of parvalbumin interneurons regulating amygdala circuit function. Mol Psychiatry. 

GluA4 – subunit containing AMPA receptors facilitate plasticity at immature synapses 

The AMPA receptor subunit GluA4 is transiently expressed in hippocampal CA1 principal neurons at the time synaptic connectivity is forming. Our research supports that GluA4 subunit confers a minimal mechanism for activity-dependent AMPA-receptor regulation to facilitate plasticity during early development of glutamatergic synapses. 

Luchkina et al. (2014). Developmental switch in the kinase dependency of long-term potentiation depends on expression of GluA4 subunit-containing AMPA receptors. Proc Natl Acad Sci USA. 111:4321.

Huupponen et al. (2016) GluA4 subunit of AMPA receptors mediates the early synaptic response to altered network activity in the developing hippocampus. J Neurophysiol.  115:2989.

Luchkina et al. (2016)  Molecular mechanisms controlling synaptic recruitment of GluA4 subunit-containing AMPA-receptors critical for functional maturation of CA1 glutamatergic synapses. Neuropharmacology 112:46. 

Our recent results show that chronic stress associates with loss of kainate receptor expression in parvalbumin – type interneurons (PV IN) in amygdala, which contributes to stress-induced PV IN malfunction and  hyperexcitability of the amygdala principal neurons.

Englund et al. (2021). Downregulation of kainate receptors regulating GABAergic transmission in amygdala after early life stress is associated with anxiety-like behavior in rodents. Transl Psychiatry 11:538.

Ryazantseva M et al. (2024) GABAB- GluK1 kainate receptor interplay modulates amygdala excitability and behavioral response to chronic stress. bioRxiv 2024.01.15.575620