UCLA

Behavioral, physiological, and anatomical evidence indicates that the dorsal and ventral zones of the hippocampus have distinct roles in cognition. How the unique functions of these zones might depend on differences in synaptic and neuronal function arising from the strikingly different gene expression profiles exhibited by dorsal and ventral CA1 pyramidal cells is unclear. To begin to address this question, I investigated the mechanisms underlying differences in synaptic transmission and plasticity at dorsal and ventral Schaffer collateral (SC) synapses.

Strikingly, although basal synaptic transmission is similar, SC synapses in the dorsal and ventral hippocampus exhibit markedly different responses to theta-frequency patterns of stimulation. In contrast to dorsal hippocampus, theta-frequency stimulation fails to elicit postsynaptic complex-spike bursting and does not induce LTP at ventral SC synapses. Moreover, EPSP-spike coupling, a process that strongly influences information transfer at synapses, is weaker in ventral pyramidal cells. All of these differences in postsynaptic function are due to an enhanced activation of SK-type K+ channels that suppresses NMDA receptor (NMDAR)-dependent EPSP amplification at ventral SC synapses. Consistent with this, mRNA levels for the SK3 subunit of SK channels are significantly higher in ventral CA1 pyramidal cells. Together, my findings indicated that a dorsal-ventral difference in SK channel regulation of NMDAR activation has a profound effect on the transmission, processing and storage of information at SC synapses and thus likely contributes to the distinct roles of the dorsal and ventral hippocampus in different behaviors. SK channel activity at dendritic spines is strongly down-regulated by -adrenergic (Carter et al. 2012) and muscarinic receptor activation (Buchanan et al. 2010; Giessel and Sabatini 2010). Thus, in addition to coincident pre- and postsynaptic activity, the induction of LTP at SC synapses in the ventral hippocampus may be highly state-dependent and require the release of modulatory neurotransmitters, such as norepinephrine or acetylcholine, to overcome the SK channel inhibition of NMDAR activation. Experiments in this dissertation focus on muscarinic neuromodulation of dorsal and ventral hippocampus and its effect on pyramidal cell excitability and LTP across dorsal-ventral axis of mouse hippocampus.