Thursday, April 18, 2024
4/18/2024
Project Summary In order to form a memory, transient experiences are captured by neurons in the brain and transformed into long-lasting changes in cell circuitry and connectivity. To elucidate the mechanisms underlying memory formation it is necessary to determine how pyramidal neuron (PN) activity is transformed into changes in the future output of the neuron. NPAS4, an immediate early gene that is expressed transiently following PN activity, has been linked to changes in inhibitory synaptic connectivity. Specifically, NPAS4 leads to recruitment of somatic CCK basket cell synapses and destabilization of dendritic inhibitory synapses. This cell-autonomous regulation of inhibitory synapses indicates that NPAS4 is a master regulator of the coordination of excitation/inhibition (E-I) balance. This biology is essential since E-I balance is associated with disorders such as epilepsy, autism, and schizophrenia. The sophisticated reorganization of inhibition initiated by NPAS4 has been shown to alter the output of CA1 PNs in acute hippocampal slice recordings, increasing the dynamic range of the PNs. In vivo, an increase in dynamic range can manifest as improved spatial tuning of CA1 place cells. While the ex vivo slice electrophysiology techniques used previously allow unparalleled access to the circuit, they do not recapitulate the firing patterns observed in vivo, particularly the distinctive tuning that characterizes CA1 place cells. Therefore, the purpose of this proposal is to determine how NPAS4 influences the in vivo firing characteristics of CA1 PNs and to identify how CCK interneurons shape those characteristics. To determine whether NPAS4 contributes to the firing characteristics of CA1 place cells in vivo, NPAS4 will be knocked out of a sparse population of optically tagged CA1 PNs, allowing for simultaneous recordings from knock out (KO) and wild-type (WT) neurons while an animal is freely moving on a track. Animals will be housed in an enriched environment (which is known to drive NPAS4 expression) to investigate how NPAS4 expression drives changes in PN firing. While it has been demonstrated in slices that NPAS4 results in recruitment of CCK basket cell synapses, it is not known how this increase in CCK basket cell inhibition shapes the in vivo firing characteristics of CA1 PNs. To explore this, a cross-sectional genetic approach will be used to selectively express an inhibitory DREADD in CA1 CCK- interneurons. Concurrently, NPAS4 KO PNs in CA1 will be optically tagged allowing for simultaneous recordings from KO and WT neurons while manipulating CCK-interneuron activity. These experiments will use in vivo techniques to better understand how NPAS4 shapes the local CA1 circuit and whether these changes occur via CCK-interneurons. In general, these findings will provide further information characterizing how regulation of inhibition impacts memory and the mechanisms that fail in neuropsychiatric and neurodevelopmental disorders.
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