Recovery of hippocampal dentate granule cell responsiveness to entorhinal cortical input following norepinephrine depletion.

Hippocampal dentate granule cell responsivity to excitatory input from entorhinal perforant path fibers was examined in the chronic rabbit preparation following norepinephrine (NE) depletion induced with the neurotoxin DSP4. To examine granule cell responsivity as a function of perforant path activation, constant low frequency stimulation (0.1 Hz) was applied to the perforant path using an ascending intensity series. To examine granule cell responsivity to more complex patterns of stimulation, a train of impulses, with a random interstimulus interval (Poisson distribution; mean frequency of 2 Hz), was applied to the perforant path. Both single impulse and random interval impulse stimulation revealed that NE depletion increased the average amplitude of the perforant path-granule cell population spike. The random interval impulse stimulation revealed that NE depletion also increased the magnitude and duration of second order inhibitory interactions. These changes were transient, however, and recovered over the 21 day test period. Hippocampal NE levels were reduced an average of 80% between 23 and 38 days post-DSP4. The activity of the rate-limiting enzyme for NE synthesis, tyrosine hydroxylase (TH), was reduced an average of 60%. That NE levels were reduced to a greater extent than was TH activity is suggestive of increased NE synthesis within the remaining nerve terminals. Such an increase in NE synthesis may reflect a compensatory response underlying the functional recovery of electrophysiological responsiveness following partial NE depletion.