INHIBITORY CIRCUITS & TARGETED MOLECULAR APPROACH FOR RESOURCE MOBILISATION

Modulation of neuronal firing rates during engram formation

Resource Mobilisation

Inhibitory circuits are key regulators of neuronal firing rates and engram formation. The precision of episodic-like memories depends on specific inhibitory interneurons and their functional maturation within perineuronal nets, other extracellular matrix proteins (ECM), and various molecular synaptic machinery. In this project, we will test a strategy to manipulate engrams via control of feedback inhibition. We will further identify mechanistic principles at the protein level that are necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.

Our previous work has led to the identification of several feedback loops and microcircuits that govern dendritic inhibition of neurons and are lead candidates for the promotion of plasticity and engram formation.
From previous work in mice we know that the precision of episodic-like memories depends on parvalbumin-containing interneurons and their functional maturation within perineuronal nets. We will test a strategy to manipulate engrams via control of feedback inhibition by ECM-targeted alterations. We will further apply this mechanistic knowledge to disease states with the goal towards pharmacological interventions to increase resource mobilisation and cognitive vitality across disease stages. We have also shown that age-dependent shifts in the precision of episodic-like memories involve the functional maturation of parvalbumin-expressing interneurons in subfield CA1 through assembly of extracellular perineuronal nets, which is necessary and sufficient for the onset of competitive neuronal allocation, sparse engram formation, and memory precision.
In a complementary approach for improving memory consolidation and recall, in this project we will also investigate the stabilisation of synaptic transmission by interfering with degradation of essential proteins such as synaptic ligand-gated ion channels. While our preliminary experiments focus on conditional expression strategies in mice, future approaches will lead us to target identification and compound screening as the synaptic and intracellular machinery offers several “druggable” pharmacological access routes.